Dominique HEYMANN
Professeur - Praticien Hospitalier Université
section 42
| Équipe : |
Thèmes de recherche
- Etude de la maladie résiduelle en oncologie: approches microfluidiques, approches translationnelles, isolement et caractérisation des évènements cellulaires rares (ex: cellules tumorales circulantes).
- Mécanismes de résistance aux drogues
- Pathogenèse des Sarcomes Osseux (approches expérimentales in vitro et in vivo)
- Différenciation ostéoclastique – Ostéolyses associées aux pathologies inflammatoires et cancéreuses – Etude du processus métastatique – Analyse de l’hétérogénéité tumorale
- Biologie des cytokines
- Fonctions extra-hémostatiques du Facteur 8
Parcours universitaire
- 1998 – HDR, Université de Nantes
- 1995 – PhD, Faculté de Médecine, INSERM U211, Université de Nantes
- 1991 – Master, Université de Paris VII, INSERM
Publications
1 publication
Jubelin, Camille; Muñoz-Garcia, Javier; Ollivier, Emilie; Cochonneau, Denis; Vallette, François; Heymann, Marie-Françoise; Oliver, Lisa; Heymann, Dominique
Identification of MCM4 and PRKDC as new regulators of osteosarcoma cell dormancy based on 3D cell cultures Article de journal
Dans: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, p. 119660, 2024, ISSN: 0167-4889.
@article{JUBELIN2024119660,
title = {Identification of MCM4 and PRKDC as new regulators of osteosarcoma cell dormancy based on 3D cell cultures},
author = {Camille Jubelin and Javier Muñoz-Garcia and Emilie Ollivier and Denis Cochonneau and François Vallette and Marie-Françoise Heymann and Lisa Oliver and Dominique Heymann},
url = {https://www.sciencedirect.com/science/article/pii/S016748892400003X},
doi = {https://doi.org/10.1016/j.bbamcr.2024.119660},
issn = {0167-4889},
year = {2024},
date = {2024-01-01},
urldate = {2024-01-01},
journal = {Biochimica et Biophysica Acta (BBA) - Molecular Cell Research},
pages = {119660},
abstract = {Dormancy is a potential way for tumors to develop drug resistance and escape treatment. However, the mechanisms involved in cancer dormancy remain poorly understood. This is mainly because there is no in vitro culture model making it possible to spontaneously induce dormancy. In this context, the present work proposes the use of three-dimensional (3D) spheroids developed from osteosarcoma cell lines as a relevant model for studying cancer dormancy. MNNG-HOS, SaOS-2, 143B, MG-63, U2OS and SJSA-1 cell lines were cultured in 3D using the Liquid Overlay Technique (LOT). Dormancy was studied by staining cancer cells with a lipophilic dye (DiD), and long-term DiD+ cells were considered as dormant cancer cells. The role of the extracellular matrix in inducing dormancy was investigated by embedding cells into methylcellulose or Geltrex™. Gene expression of DiD+ cells was assessed with a Nanostring™ approach and the role of the genes detected in dormancy was validated by a transient down-expression model using siRNA treatment. Proliferation was measured using fluorescence microscopy and the xCELLigence technology. We observed that MNNG-HOS, 143B and MG-G3 cell lines had a reduced proliferation rate in 3D compared to 2D. U2OS cells had an increased proliferation rate when they were cultured in Geltrex™ compared to other 3D culture methods. Using 3D cultures, a transcriptomic signature of dormancy was obtained and showed a decreased expression of 18 genes including ETV4, HELLS, ITGA6, MCM4, PRKDC, RAD21 and UBE2T. The treatment with siRNA targeting these genes showed that cancer cell proliferation was reduced when the expression of ETV4 and MCM4 were decreased, whereas proliferation was increased when the expression of RAD21 was decreased. 3D culture facilitates the maintenance of dormant cancer cells characterized by a reduced proliferation and less differential gene expression as compared to proliferative cells. Further studies of the genes involved has enabled us to envisage their role in regulating cell proliferation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dormancy is a potential way for tumors to develop drug resistance and escape treatment. However, the mechanisms involved in cancer dormancy remain poorly understood. This is mainly because there is no in vitro culture model making it possible to spontaneously induce dormancy. In this context, the present work proposes the use of three-dimensional (3D) spheroids developed from osteosarcoma cell lines as a relevant model for studying cancer dormancy. MNNG-HOS, SaOS-2, 143B, MG-63, U2OS and SJSA-1 cell lines were cultured in 3D using the Liquid Overlay Technique (LOT). Dormancy was studied by staining cancer cells with a lipophilic dye (DiD), and long-term DiD+ cells were considered as dormant cancer cells. The role of the extracellular matrix in inducing dormancy was investigated by embedding cells into methylcellulose or Geltrex™. Gene expression of DiD+ cells was assessed with a Nanostring™ approach and the role of the genes detected in dormancy was validated by a transient down-expression model using siRNA treatment. Proliferation was measured using fluorescence microscopy and the xCELLigence technology. We observed that MNNG-HOS, 143B and MG-G3 cell lines had a reduced proliferation rate in 3D compared to 2D. U2OS cells had an increased proliferation rate when they were cultured in Geltrex™ compared to other 3D culture methods. Using 3D cultures, a transcriptomic signature of dormancy was obtained and showed a decreased expression of 18 genes including ETV4, HELLS, ITGA6, MCM4, PRKDC, RAD21 and UBE2T. The treatment with siRNA targeting these genes showed that cancer cell proliferation was reduced when the expression of ETV4 and MCM4 were decreased, whereas proliferation was increased when the expression of RAD21 was decreased. 3D culture facilitates the maintenance of dormant cancer cells characterized by a reduced proliferation and less differential gene expression as compared to proliferative cells. Further studies of the genes involved has enabled us to envisage their role in regulating cell proliferation.
8 publications
Panez-Toro, Isidora; Heymann, Dominique; Gouin, François; Amiaud, Jérôme; Heymann, Marie-Françoise; Córdova, Luis A.
Roles of inflammatory cell infiltrate in periprosthetic osteolysis Article de journal
Dans: Frontiers in Immunology, vol. 14, p. 1310262, 2023, ISSN: 1664-3224.
@article{panez-toro_roles_2023,
title = {Roles of inflammatory cell infiltrate in periprosthetic osteolysis},
author = {Isidora Panez-Toro and Dominique Heymann and François Gouin and Jérôme Amiaud and Marie-Françoise Heymann and Luis A. Córdova},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1310262/full},
doi = {10.3389/fimmu.2023.1310262},
issn = {1664-3224},
year = {2023},
date = {2023-12-01},
urldate = {2023-12-01},
journal = {Frontiers in Immunology},
volume = {14},
pages = {1310262},
abstract = {Classically, particle-induced periprosthetic osteolysis at the implant–bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3+
, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP−multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Classically, particle-induced periprosthetic osteolysis at the implant–bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3+
, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP−multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.
, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP−multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.
Dubois, Nolwenn; Muñoz-Garcia, Javier; Heymann, Dominique; Renodon-Cornière, Axelle
High glucose exposure drives intestinal barrier dysfunction by altering its morphological, structural and functional properties. Article de journal
Dans: Biochemical pharmacology, vol. 216, p. 115765, 2023, ISSN: 1873-2968 0006-2952, (Place: England).
@article{dubois_high_2023,
title = {High glucose exposure drives intestinal barrier dysfunction by altering its morphological, structural and functional properties.},
author = {Nolwenn Dubois and Javier Muñoz-Garcia and Dominique Heymann and Axelle Renodon-Cornière},
doi = {10.1016/j.bcp.2023.115765},
issn = {1873-2968 0006-2952},
year = {2023},
date = {2023-10-01},
urldate = {2023-10-01},
journal = {Biochemical pharmacology},
volume = {216},
pages = {115765},
abstract = {High dietary glucose consumption and hyperglycemia can result in chronic complications. Several studies suggest that high glucose (HG) induces dysfunction of the intestinal barrier. However, the precise changes remain unclear. In our study, we used in vitro models composed of Caco-2 and/or HT29-MTX cells in both monoculture and co-culture to assess the effects of long-term HG exposure on the morphological, structural, and functional properties of the intestinal barrier. Cells were grown in medium containing normal physiologic glucose (NG, 5.5 mM) or a clinically relevant HG (25 mM) concentration until 21 days. Results demonstrated that HG induced morphological changes, with the layers appearing denser and less organized than under physiological conditions, which is in accordance with the increased migration capacity of Caco-2 cells and proliferation properties of HT29-MTX cells. Although we mostly observed a small decrease in mRNA and protein expressions of three junction proteins (ZO-1, OCLN and E-cad) in both Caco-2 and HT29-MTX cells cultured in HG medium, confocal microscopy showed that HG induced a remarkable reduction in their immunofluorescence intensity, triggering disruption of their associated structural network. In addition, we highlighted that HG affected different functionalities (permeability, mucus production and alkaline phosphatase activity) of monolayers with Caco-2 and HT29-MTX cells. Interestingly, these alterations were stronger in co-culture than in monoculture, suggesting a cross-relationship between enterocytes and goblet cells. Controlling hyperglycemia remains a major therapeutical method for reducing damage to the intestinal barrier and improving therapies.},
note = {Place: England},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
High dietary glucose consumption and hyperglycemia can result in chronic complications. Several studies suggest that high glucose (HG) induces dysfunction of the intestinal barrier. However, the precise changes remain unclear. In our study, we used in vitro models composed of Caco-2 and/or HT29-MTX cells in both monoculture and co-culture to assess the effects of long-term HG exposure on the morphological, structural, and functional properties of the intestinal barrier. Cells were grown in medium containing normal physiologic glucose (NG, 5.5 mM) or a clinically relevant HG (25 mM) concentration until 21 days. Results demonstrated that HG induced morphological changes, with the layers appearing denser and less organized than under physiological conditions, which is in accordance with the increased migration capacity of Caco-2 cells and proliferation properties of HT29-MTX cells. Although we mostly observed a small decrease in mRNA and protein expressions of three junction proteins (ZO-1, OCLN and E-cad) in both Caco-2 and HT29-MTX cells cultured in HG medium, confocal microscopy showed that HG induced a remarkable reduction in their immunofluorescence intensity, triggering disruption of their associated structural network. In addition, we highlighted that HG affected different functionalities (permeability, mucus production and alkaline phosphatase activity) of monolayers with Caco-2 and HT29-MTX cells. Interestingly, these alterations were stronger in co-culture than in monoculture, suggesting a cross-relationship between enterocytes and goblet cells. Controlling hyperglycemia remains a major therapeutical method for reducing damage to the intestinal barrier and improving therapies.
Pu, Yi; Li, Lu; Peng, Haoning; Liu, Lunxu; Heymann, Dominique; Robert, Caroline; Vallette, François; Shen, Shensi
Drug-tolerant persister cells in cancer: the cutting edges and future directions Article de journal
Dans: Nature Reviews Clinical Oncology, 2023, ISSN: 1759-4782.
@article{pu_drug-tolerant_2023,
title = {Drug-tolerant persister cells in cancer: the cutting edges and future directions},
author = {Yi Pu and Lu Li and Haoning Peng and Lunxu Liu and Dominique Heymann and Caroline Robert and François Vallette and Shensi Shen},
url = {https://doi.org/10.1038/s41571-023-00815-5},
doi = {10.1038/s41571-023-00815-5},
issn = {1759-4782},
year = {2023},
date = {2023-09-01},
urldate = {2023-09-01},
journal = {Nature Reviews Clinical Oncology},
abstract = {Drug-tolerant persister (DTP) cell populations were originally discovered in antibiotic-resistant bacterial biofilms. Similar populations with comparable features have since been identified among cancer cells and have been linked with treatment resistance that lacks an underlying genomic alteration. Research over the past decade has improved our understanding of the biological roles of DTP cells in cancer, although clinical knowledge of the role of these cells in treatment resistance remains limited. Nonetheless, targeting this population is anticipated to provide new treatment opportunities. In this Perspective, we aim to provide a clear definition of the DTP phenotype, discuss the underlying characteristics of these cells, their biomarkers and vulnerabilities, and encourage further research on DTP cells that might improve our understanding and enable the development of more effective anticancer therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Drug-tolerant persister (DTP) cell populations were originally discovered in antibiotic-resistant bacterial biofilms. Similar populations with comparable features have since been identified among cancer cells and have been linked with treatment resistance that lacks an underlying genomic alteration. Research over the past decade has improved our understanding of the biological roles of DTP cells in cancer, although clinical knowledge of the role of these cells in treatment resistance remains limited. Nonetheless, targeting this population is anticipated to provide new treatment opportunities. In this Perspective, we aim to provide a clear definition of the DTP phenotype, discuss the underlying characteristics of these cells, their biomarkers and vulnerabilities, and encourage further research on DTP cells that might improve our understanding and enable the development of more effective anticancer therapies.
Panez-Toro, Isidora; Muñoz-García, Javier; Vargas-Franco, Jorge W.; Renodon-Cornière, Axelle; Heymann, Marie-Françoise; Lézot, Frédéric; Heymann, Dominique
Advances in Osteosarcoma Article de journal
Dans: Current Osteoporosis Reports, 2023, ISSN: 1544-1873, 1544-2241.
@article{panez-toro_advances_2023,
title = {Advances in Osteosarcoma},
author = {Isidora Panez-Toro and Javier Muñoz-García and Jorge W. Vargas-Franco and Axelle Renodon-Cornière and Marie-Françoise Heymann and Frédéric Lézot and Dominique Heymann},
url = {https://link.springer.com/10.1007/s11914-023-00803-9},
doi = {10.1007/s11914-023-00803-9},
issn = {1544-1873, 1544-2241},
year = {2023},
date = {2023-06-01},
urldate = {2023-06-01},
journal = {Current Osteoporosis Reports},
abstract = {Purpose of Review
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
Recent Findings
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme.
Summary
The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose of Review
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
Recent Findings
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme.
Summary
The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
Recent Findings
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme.
Summary
The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.
Loussouarn, Delphine; Oliver, Lisa; Salaud, Celine; Samarut, Edouard; Bourgade, Raphaël; Béroud, Christophe; Morenton, Emilie; Heymann, Dominique; Vallette, Francois M.
Spatial Distribution of Immune Cells in Primary and Recurrent Glioblastoma: A Small Case Study Article de journal
Dans: Cancers, vol. 15, no. 12, p. 3256, 2023, ISSN: 2072-6694.
@article{loussouarn_spatial_2023,
title = {Spatial Distribution of Immune Cells in Primary and Recurrent Glioblastoma: A Small Case Study},
author = {Delphine Loussouarn and Lisa Oliver and Celine Salaud and Edouard Samarut and Raphaël Bourgade and Christophe Béroud and Emilie Morenton and Dominique Heymann and Francois M. Vallette},
url = {https://www.mdpi.com/2072-6694/15/12/3256},
doi = {10.3390/cancers15123256},
issn = {2072-6694},
year = {2023},
date = {2023-06-01},
urldate = {2023-06-01},
journal = {Cancers},
volume = {15},
number = {12},
pages = {3256},
abstract = {Only a minority of patients with glioblastoma (GBM) respond to immunotherapy, and always only partially. There is a lack of knowledge on immune distribution in GBM and in its tumor microenvironment (TME). To address the question, we used paired primary and recurrent tumors from GBM patients to study the composition and the evolution of the immune landscape upon treatment. We studied the expression of a handful of immune markers (CD3, CD8, CD68, PD-L1 and PD-1) in GBM tissues in 15 paired primary and recurrent GBM. In five selected patients, we used Nanostring Digital Spatial Profiling (DSP) to obtain simultaneous assessments of multiple biomarkers both within the tumor and the microenvironment in paired primary and recurrent GBM. Our results suggest that the evolution of the immune landscape between paired primary and recurrent GBM tumors is highly heterogeneous. However, our study identifies B3-H7 and HLA-DR as potential targets in primary and recurrent GBM. Spatial profiling of immune markers from matched primary and recurrent GBM shows a nonlinear complex evolution during the progression of cancer. Nonetheless, our study demonstrated a global increase in macrophages, and revealed differential localization of some markers, such as B7-H3 and HLA-DR, between GBM and its TME.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Only a minority of patients with glioblastoma (GBM) respond to immunotherapy, and always only partially. There is a lack of knowledge on immune distribution in GBM and in its tumor microenvironment (TME). To address the question, we used paired primary and recurrent tumors from GBM patients to study the composition and the evolution of the immune landscape upon treatment. We studied the expression of a handful of immune markers (CD3, CD8, CD68, PD-L1 and PD-1) in GBM tissues in 15 paired primary and recurrent GBM. In five selected patients, we used Nanostring Digital Spatial Profiling (DSP) to obtain simultaneous assessments of multiple biomarkers both within the tumor and the microenvironment in paired primary and recurrent GBM. Our results suggest that the evolution of the immune landscape between paired primary and recurrent GBM tumors is highly heterogeneous. However, our study identifies B3-H7 and HLA-DR as potential targets in primary and recurrent GBM. Spatial profiling of immune markers from matched primary and recurrent GBM shows a nonlinear complex evolution during the progression of cancer. Nonetheless, our study demonstrated a global increase in macrophages, and revealed differential localization of some markers, such as B7-H3 and HLA-DR, between GBM and its TME.
Madel, Maria-Bernadette; Halper, Julia; Ibáñez, Lidia; Claire, Lozano; Rouleau, Matthieu; Boutin, Antoine; Mahler, Adrien; Pontier-Bres, Rodolphe; Ciucci, Thomas; Topi, Majlinda; Hue, Christophe; Amiaud, Jerome; Iborra, Salvador; Sancho, David; Heymann, Dominique; Garchon, Henri-Jean; Czerucka, Dorota; Apparailly, Florence; Duroux-Richard, Isabelle; Wakkach, Abdelilah; Blin-Wakkach, Claudine
Specific targeting of inflammatory osteoclastogenesis by the probiotic yeast S. boulardii CNCM I-745 reduces bone loss in osteoporosis Article de journal
Dans: eLife, vol. 12, p. e82037, 2023, ISSN: 2050-084X.
@article{10.7554/eLife.82037,
title = {Specific targeting of inflammatory osteoclastogenesis by the probiotic yeast S. boulardii CNCM I-745 reduces bone loss in osteoporosis},
author = {Maria-Bernadette Madel and Julia Halper and Lidia Ibáñez and Lozano Claire and Matthieu Rouleau and Antoine Boutin and Adrien Mahler and Rodolphe Pontier-Bres and Thomas Ciucci and Majlinda Topi and Christophe Hue and Jerome Amiaud and Salvador Iborra and David Sancho and Dominique Heymann and Henri-Jean Garchon and Dorota Czerucka and Florence Apparailly and Isabelle Duroux-Richard and Abdelilah Wakkach and Claudine Blin-Wakkach},
editor = {Yi-Ping Li and Mone Zaidi and Marco Ponzetti},
url = {https://doi.org/10.7554/eLife.82037},
doi = {10.7554/eLife.82037},
issn = {2050-084X},
year = {2023},
date = {2023-02-01},
urldate = {2023-02-01},
journal = {eLife},
volume = {12},
pages = {e82037},
publisher = {eLife Sciences Publications, Ltd},
abstract = {Bone destruction is a hallmark of chronic inflammation, and bone-resorbing osteoclasts arising under such a condition differ from steady-state ones. However, osteoclast diversity remains poorly explored. Here, we combined transcriptomic profiling, differentiation assays and in vivo analysis in mouse to decipher specific traits for inflammatory and steady-state osteoclasts. We identified and validated the pattern-recognition receptors (PRR) Tlr2, Dectin-1, and Mincle, all involved in yeast recognition as major regulators of inflammatory osteoclasts. We showed that administration of the yeast probiotic textitSaccharomyces boulardii CNCM I-745 (textitSb) in vivo reduced bone loss in ovariectomized but not sham mice by reducing inflammatory osteoclastogenesis. This beneficial impact of textitSb is mediated by the regulation of the inflammatory environment required for the generation of inflammatory osteoclasts. We also showed that textitSb derivatives as well as agonists of Tlr2, Dectin-1, and Mincle specifically inhibited directly the differentiation of inflammatory but not steady-state osteoclasts in vitro. These findings demonstrate a preferential use of the PRR-associated costimulatory differentiation pathway by inflammatory osteoclasts, thus enabling their specific inhibition, which opens new therapeutic perspectives for inflammatory bone loss.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Bone destruction is a hallmark of chronic inflammation, and bone-resorbing osteoclasts arising under such a condition differ from steady-state ones. However, osteoclast diversity remains poorly explored. Here, we combined transcriptomic profiling, differentiation assays and in vivo analysis in mouse to decipher specific traits for inflammatory and steady-state osteoclasts. We identified and validated the pattern-recognition receptors (PRR) Tlr2, Dectin-1, and Mincle, all involved in yeast recognition as major regulators of inflammatory osteoclasts. We showed that administration of the yeast probiotic textitSaccharomyces boulardii CNCM I-745 (textitSb) in vivo reduced bone loss in ovariectomized but not sham mice by reducing inflammatory osteoclastogenesis. This beneficial impact of textitSb is mediated by the regulation of the inflammatory environment required for the generation of inflammatory osteoclasts. We also showed that textitSb derivatives as well as agonists of Tlr2, Dectin-1, and Mincle specifically inhibited directly the differentiation of inflammatory but not steady-state osteoclasts in vitro. These findings demonstrate a preferential use of the PRR-associated costimulatory differentiation pathway by inflammatory osteoclasts, thus enabling their specific inhibition, which opens new therapeutic perspectives for inflammatory bone loss.
Oliver, Lisa; Álvarez-Arenas, Arturo; Salaud, Céline; Jiménez-Sanchez, Juan; Calvo, Gabriel F.; Belmonte-Beitia, Juan; Blandin, Stephanie; Vidal, Luciano; Pérez, Victor; Heymann, Dominique; Vallette, François M.
A Simple 3D Cell Culture Method for Studying the Interactions between Human Mesenchymal Stromal/Stem Cells and Patients Derived Glioblastoma Article de journal
Dans: Cancers, vol. 15, no. 4, 2023, ISSN: 2072-6694.
@article{cancers15041304,
title = {A Simple 3D Cell Culture Method for Studying the Interactions between Human Mesenchymal Stromal/Stem Cells and Patients Derived Glioblastoma},
author = {Lisa Oliver and Arturo Álvarez-Arenas and Céline Salaud and Juan Jiménez-Sanchez and Gabriel F. Calvo and Juan Belmonte-Beitia and Stephanie Blandin and Luciano Vidal and Victor Pérez and Dominique Heymann and François M. Vallette},
url = {https://www.mdpi.com/2072-6694/15/4/1304},
doi = {10.3390/cancers15041304},
issn = {2072-6694},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Cancers},
volume = {15},
number = {4},
abstract = {We have developed a 3D biosphere model using patient-derived cells (PDCs) from glioblastoma (GBM), the major form of primary brain tumors in adult, plus cancer-activated fibroblasts (CAFs), obtained by culturing mesenchymal stem cells with GBM conditioned media. The effect of MSC/CAFs on the proliferation, cell-cell interactions, and response to treatment of PDCs was evaluated. Proliferation in the presence of CAFs was statistically lower but the spheroids formed within the 3D-biosphere were larger. A treatment for 5 days with Temozolomide (TMZ) and irradiation, the standard therapy for GBM, had a marked effect on cell number in monocultures compared to co-cultures and influenced cancer stem cells composition, similar to that observed in GBM patients. Mathematical analyses of spheroids growth and morphology confirm the similarity with GBM patients. We, thus, provide a simple and reproducible method to obtain 3D cultures from patient-derived biopsies and co-cultures with MSC with a near 100% success. This method provides the basis for relevant in vitro functional models for a better comprehension of the role of tumor microenvironment and, for precision and/or personalized medicine, potentially to predict the response to treatments for each GBM patient.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We have developed a 3D biosphere model using patient-derived cells (PDCs) from glioblastoma (GBM), the major form of primary brain tumors in adult, plus cancer-activated fibroblasts (CAFs), obtained by culturing mesenchymal stem cells with GBM conditioned media. The effect of MSC/CAFs on the proliferation, cell-cell interactions, and response to treatment of PDCs was evaluated. Proliferation in the presence of CAFs was statistically lower but the spheroids formed within the 3D-biosphere were larger. A treatment for 5 days with Temozolomide (TMZ) and irradiation, the standard therapy for GBM, had a marked effect on cell number in monocultures compared to co-cultures and influenced cancer stem cells composition, similar to that observed in GBM patients. Mathematical analyses of spheroids growth and morphology confirm the similarity with GBM patients. We, thus, provide a simple and reproducible method to obtain 3D cultures from patient-derived biopsies and co-cultures with MSC with a near 100% success. This method provides the basis for relevant in vitro functional models for a better comprehension of the role of tumor microenvironment and, for precision and/or personalized medicine, potentially to predict the response to treatments for each GBM patient.
Jacquot, Perrine; Muñoz-Garcia, Javier; Fleury, Maurine; Cochonneau, Denis; Gaussin, Rémi; Enouf, Elise; Roze, Caroline; Ollivier, Emilie; Cinier, Mathieu; Heymann, Dominique
Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 Article de journal
Dans: Biomolecules, vol. 13, no. 4, 2023, ISSN: 2218-273X.
@article{biom13040636,
title = {Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1},
author = {Perrine Jacquot and Javier Muñoz-Garcia and Maurine Fleury and Denis Cochonneau and Rémi Gaussin and Elise Enouf and Caroline Roze and Emilie Ollivier and Mathieu Cinier and Dominique Heymann},
url = {https://www.mdpi.com/2218-273X/13/4/636},
doi = {10.3390/biom13040636},
issn = {2218-273X},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Biomolecules},
volume = {13},
number = {4},
abstract = {Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell's selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell's selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition.
11 publications
Beird, Hannah C; Bielack, Stefan S; Flanagan, Adrienne M; Gill, Jonathan; Heymann, Dominique; Janeway, Katherine A; Livingston, J Andrew; Roberts, Ryan D; Strauss, Sandra J; Gorlick, Richard
Osteosarcoma Article de journal
Dans: Nat Rev Dis Primers, vol. 8, no. 1, p. 77, 2022, ISSN: 2056-676X.
@article{pmid36481668,
title = {Osteosarcoma},
author = {Hannah C Beird and Stefan S Bielack and Adrienne M Flanagan and Jonathan Gill and Dominique Heymann and Katherine A Janeway and J Andrew Livingston and Ryan D Roberts and Sandra J Strauss and Richard Gorlick},
doi = {10.1038/s41572-022-00409-y},
issn = {2056-676X},
year = {2022},
date = {2022-12-01},
urldate = {2022-12-01},
journal = {Nat Rev Dis Primers},
volume = {8},
number = {1},
pages = {77},
abstract = {Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
Heymann, Clément J F; Bobin-Dubigeon, Christine; Muñoz-Garcia, Javier; Cochonneau, Denis; Ollivier, Emilie; Heymann, Marie-Françoise; Heymann, Dominique
Lipopolysaccharide-binding protein expression is associated to the metastatic status of osteosarcoma patients Article de journal
Dans: J Bone Oncol, vol. 36, p. 100451, 2022, ISSN: 2212-1366.
@article{pmid35990515,
title = {Lipopolysaccharide-binding protein expression is associated to the metastatic status of osteosarcoma patients},
author = {Clément J F Heymann and Christine Bobin-Dubigeon and Javier Muñoz-Garcia and Denis Cochonneau and Emilie Ollivier and Marie-Françoise Heymann and Dominique Heymann},
doi = {10.1016/j.jbo.2022.100451},
issn = {2212-1366},
year = {2022},
date = {2022-10-01},
urldate = {2022-10-01},
journal = {J Bone Oncol},
volume = {36},
pages = {100451},
abstract = {Osteosarcoma (OS) is a rare malignant primary bone tumours characterized by a high genetic and cell composition heterogeneity. Unfortunately, despite the use of drug combinations and the recent development of immunotherapies, the overall survival has not improved in the last four decades. Due to the key role of the tumour microenvironment in the pathogenesis of OS, a better understanding of its microenvironment is mandatory to develop new therapeutic approaches. From retrospective biological cohorts of OS, we analysed by immunohistochemistry the presence of lipopolysaccharide (LPS)-binding protein (LBP) in diagnostic biopsies with local disease and compared their level of infiltration to patients suffering from metastatic status. LBP is considered as a marker of LPS exposure and can indirectly reflect the presence of Gram-negative microbiota. LBP were detected in the cytoplasm of OS cells as well as in tumour-associated macrophage. Tumour samples of patients with local disease were significantly enriched in LBP compared to tumour tissues of patients with metastatic status. Lung metastatic tissues showed similar level of LBP compared to paired primary tumours. Overall, this study strongly suggests the presence of Gram-negative bacteria in OS tissues and demonstrated their significant differential level according the metastatic status. This tumour-associated microbiome may help in the conceptualisation of new therapeutic approach to trigger efficient therapeutic responses against cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Osteosarcoma (OS) is a rare malignant primary bone tumours characterized by a high genetic and cell composition heterogeneity. Unfortunately, despite the use of drug combinations and the recent development of immunotherapies, the overall survival has not improved in the last four decades. Due to the key role of the tumour microenvironment in the pathogenesis of OS, a better understanding of its microenvironment is mandatory to develop new therapeutic approaches. From retrospective biological cohorts of OS, we analysed by immunohistochemistry the presence of lipopolysaccharide (LPS)-binding protein (LBP) in diagnostic biopsies with local disease and compared their level of infiltration to patients suffering from metastatic status. LBP is considered as a marker of LPS exposure and can indirectly reflect the presence of Gram-negative microbiota. LBP were detected in the cytoplasm of OS cells as well as in tumour-associated macrophage. Tumour samples of patients with local disease were significantly enriched in LBP compared to tumour tissues of patients with metastatic status. Lung metastatic tissues showed similar level of LBP compared to paired primary tumours. Overall, this study strongly suggests the presence of Gram-negative bacteria in OS tissues and demonstrated their significant differential level according the metastatic status. This tumour-associated microbiome may help in the conceptualisation of new therapeutic approach to trigger efficient therapeutic responses against cancer.
Rodríguez-Pena, Alejandro; Armendariz, Estibaliz; Oyarbide, Alvaro; Morales, Xabier; Ortiz-Espinosa, Sergio; de Córdoba, Borja Ruiz-Fernández; Cochonneau, Denis; Cornago, Iñaki; Heymann, Dominique; Argemi, Josepmaría; D'Avola, Delia; Sangro, Bruno; Lecanda, Fernando; Pio, Ruben; Cortés-Domínguez, Iván; Ortiz-de-Solórzano, Carlos
Design and validation of a tunable inertial microfluidic system for the efficient enrichment of circulating tumor cells in blood Article de journal
Dans: Bioeng Transl Med, vol. 7, no. 3, p. e10331, 2022, ISSN: 2380-6761.
@article{pmid36176621,
title = {Design and validation of a tunable inertial microfluidic system for the efficient enrichment of circulating tumor cells in blood},
author = {Alejandro Rodríguez-Pena and Estibaliz Armendariz and Alvaro Oyarbide and Xabier Morales and Sergio Ortiz-Espinosa and Borja Ruiz-Fernández de Córdoba and Denis Cochonneau and Iñaki Cornago and Dominique Heymann and Josepmaría Argemi and Delia D'Avola and Bruno Sangro and Fernando Lecanda and Ruben Pio and Iván Cortés-Domínguez and Carlos Ortiz-de-Solórzano},
doi = {10.1002/btm2.10331},
issn = {2380-6761},
year = {2022},
date = {2022-09-01},
urldate = {2022-09-01},
journal = {Bioeng Transl Med},
volume = {7},
number = {3},
pages = {e10331},
abstract = {The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising high-throughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cut-off value of 9 μm and a separation range of 2 μm. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut-off value and better separation results than the state of the art.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising high-throughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cut-off value of 9 μm and a separation range of 2 μm. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut-off value and better separation results than the state of the art.
Jubelin, Camille; Muñoz-Garcia, Javier; Griscom, Laurent; Cochonneau, Denis; Ollivier, Emilie; Heymann, Marie-Françoise; Vallette, François M; Oliver, Lisa; Heymann, Dominique
Three-dimensional in vitro culture models in oncology research Article de journal
Dans: Cell Biosci, vol. 12, no. 1, p. 155, 2022, ISSN: 2045-3701.
@article{pmid36089610,
title = {Three-dimensional in vitro culture models in oncology research},
author = {Camille Jubelin and Javier Muñoz-Garcia and Laurent Griscom and Denis Cochonneau and Emilie Ollivier and Marie-Françoise Heymann and François M Vallette and Lisa Oliver and Dominique Heymann},
doi = {10.1186/s13578-022-00887-3},
issn = {2045-3701},
year = {2022},
date = {2022-09-01},
urldate = {2022-09-01},
journal = {Cell Biosci},
volume = {12},
number = {1},
pages = {155},
abstract = {Cancer is a multifactorial disease that is responsible for 10 million deaths per year. The intra- and inter-heterogeneity of malignant tumors make it difficult to develop single targeted approaches. Similarly, their diversity requires various models to investigate the mechanisms involved in cancer initiation, progression, drug resistance and recurrence. Of the in vitro cell-based models, monolayer adherent (also known as 2D culture) cell cultures have been used for the longest time. However, it appears that they are often less appropriate than the three-dimensional (3D) cell culture approach for mimicking the biological behavior of tumor cells, in particular the mechanisms leading to therapeutic escape and drug resistance. Multicellular tumor spheroids are widely used to study cancers in 3D, and can be generated by a multiplicity of techniques, such as liquid-based and scaffold-based 3D cultures, microfluidics and bioprinting. Organoids are more complex 3D models than multicellular tumor spheroids because they are generated from stem cells isolated from patients and are considered as powerful tools to reproduce the disease development in vitro. The present review provides an overview of the various 3D culture models that have been set up to study cancer development and drug response. The advantages of 3D models compared to 2D cell cultures, the constraint, and the fields of application of these models and their techniques of production are also discussed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cancer is a multifactorial disease that is responsible for 10 million deaths per year. The intra- and inter-heterogeneity of malignant tumors make it difficult to develop single targeted approaches. Similarly, their diversity requires various models to investigate the mechanisms involved in cancer initiation, progression, drug resistance and recurrence. Of the in vitro cell-based models, monolayer adherent (also known as 2D culture) cell cultures have been used for the longest time. However, it appears that they are often less appropriate than the three-dimensional (3D) cell culture approach for mimicking the biological behavior of tumor cells, in particular the mechanisms leading to therapeutic escape and drug resistance. Multicellular tumor spheroids are widely used to study cancers in 3D, and can be generated by a multiplicity of techniques, such as liquid-based and scaffold-based 3D cultures, microfluidics and bioprinting. Organoids are more complex 3D models than multicellular tumor spheroids because they are generated from stem cells isolated from patients and are considered as powerful tools to reproduce the disease development in vitro. The present review provides an overview of the various 3D culture models that have been set up to study cancer development and drug response. The advantages of 3D models compared to 2D cell cultures, the constraint, and the fields of application of these models and their techniques of production are also discussed.
Ollivier, Luc; Orione, Charles; Bore, Paul; Misery, Laurent; Legoupil, Delphine; Leclere, Jean-Christophe; Coste, Anne; Girault, Gilles; Sicard-Cras, Iona; Kacperek, Clemence; Lucia, Francois; Stefan, Dinu; Thillays, François; Rio, Emmanuel; Lesueur, Paul; Berthou, Christian; Heymann, Dominique; Champiat, Stéphane; Supiot, Stéphane; Vaugier, Loig; Kao, William
Abscopal Response in Metastatic Melanoma: Real-World Data of a Retrospective, Multicenter Study Article de journal
Dans: Cancers (Basel), vol. 14, no. 17, 2022, ISSN: 2072-6694.
@article{pmid36077747,
title = {Abscopal Response in Metastatic Melanoma: Real-World Data of a Retrospective, Multicenter Study},
author = {Luc Ollivier and Charles Orione and Paul Bore and Laurent Misery and Delphine Legoupil and Jean-Christophe Leclere and Anne Coste and Gilles Girault and Iona Sicard-Cras and Clemence Kacperek and Francois Lucia and Dinu Stefan and François Thillays and Emmanuel Rio and Paul Lesueur and Christian Berthou and Dominique Heymann and Stéphane Champiat and Stéphane Supiot and Loig Vaugier and William Kao},
doi = {10.3390/cancers14174213},
issn = {2072-6694},
year = {2022},
date = {2022-08-01},
urldate = {2022-08-01},
journal = {Cancers (Basel)},
volume = {14},
number = {17},
abstract = {OBJECTIVE: To evaluate the incidence of the abscopal response (AR) in patients with metastatic melanoma requiring palliative radiotherapy (RT).
PATIENTS AND METHODS: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under immune checkpoint inhibitors or without ongoing systemic treatment, and requiring palliative RT were considered. The AR was defined as an objective response according to RECIST and/or iRECIST for at least one non-irradiated metastasis at distance (≥10 cm) from the irradiated lesion. Primary endpoint was the rate of AR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), local control (LC) of the irradiated lesion, and toxicity as assessed by CTCAE v5.
RESULTS: Over the period considered, 118 patients were included and analyzed. Fifteen patients (12.7%) had an AR. With a median follow-up of 7.7 months (range, 0.2-242.2), median OS and PFS after RT were significantly longer in patients with an AR compared to those without: 28 vs. 6.6 months ( < 0.01) and not reached vs. .2 months, respectively. No grade ≥2 toxicity was reported. Patients who developed an AR were more likely to be treated with immunotherapy (93.3% vs. 55.9%, 0.02). In multivariate analysis, they had a higher number of irradiated metastases treated concomitantly (HR = 16.9, < 0.01) and a higher rate of mild infections during RT (HR = 403.5, < 0.01).
CONCLUSIONS: AR in metastatic melanoma seems to be highly prognostic of overall survival, although it is a rare phenomenon. It may be promoted by multiple concomitant treatments with RT and immunotherapy and by acute inflammatory events such as infection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: To evaluate the incidence of the abscopal response (AR) in patients with metastatic melanoma requiring palliative radiotherapy (RT).
PATIENTS AND METHODS: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under immune checkpoint inhibitors or without ongoing systemic treatment, and requiring palliative RT were considered. The AR was defined as an objective response according to RECIST and/or iRECIST for at least one non-irradiated metastasis at distance (≥10 cm) from the irradiated lesion. Primary endpoint was the rate of AR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), local control (LC) of the irradiated lesion, and toxicity as assessed by CTCAE v5.
RESULTS: Over the period considered, 118 patients were included and analyzed. Fifteen patients (12.7%) had an AR. With a median follow-up of 7.7 months (range, 0.2-242.2), median OS and PFS after RT were significantly longer in patients with an AR compared to those without: 28 vs. 6.6 months ( < 0.01) and not reached vs. .2 months, respectively. No grade ≥2 toxicity was reported. Patients who developed an AR were more likely to be treated with immunotherapy (93.3% vs. 55.9%, 0.02). In multivariate analysis, they had a higher number of irradiated metastases treated concomitantly (HR = 16.9, < 0.01) and a higher rate of mild infections during RT (HR = 403.5, < 0.01).
CONCLUSIONS: AR in metastatic melanoma seems to be highly prognostic of overall survival, although it is a rare phenomenon. It may be promoted by multiple concomitant treatments with RT and immunotherapy and by acute inflammatory events such as infection.
PATIENTS AND METHODS: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under immune checkpoint inhibitors or without ongoing systemic treatment, and requiring palliative RT were considered. The AR was defined as an objective response according to RECIST and/or iRECIST for at least one non-irradiated metastasis at distance (≥10 cm) from the irradiated lesion. Primary endpoint was the rate of AR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), local control (LC) of the irradiated lesion, and toxicity as assessed by CTCAE v5.
RESULTS: Over the period considered, 118 patients were included and analyzed. Fifteen patients (12.7%) had an AR. With a median follow-up of 7.7 months (range, 0.2-242.2), median OS and PFS after RT were significantly longer in patients with an AR compared to those without: 28 vs. 6.6 months ( < 0.01) and not reached vs. .2 months, respectively. No grade ≥2 toxicity was reported. Patients who developed an AR were more likely to be treated with immunotherapy (93.3% vs. 55.9%, 0.02). In multivariate analysis, they had a higher number of irradiated metastases treated concomitantly (HR = 16.9, < 0.01) and a higher rate of mild infections during RT (HR = 403.5, < 0.01).
CONCLUSIONS: AR in metastatic melanoma seems to be highly prognostic of overall survival, although it is a rare phenomenon. It may be promoted by multiple concomitant treatments with RT and immunotherapy and by acute inflammatory events such as infection.
Jubelin, Camille; Cochonneau, Denis; Moranton, Emilie; Munoz-Garcia, Javier; Heymann, Dominique
Circulating Tumor Cells and ctDNA in Sarcomas Chapitre d'ouvrage
Dans: Leong, Stanley P.; Nathanson, S. David; Zager, Jonathan S. (Ed.): Cancer Metastasis Through the Lymphovascular System, p. 121–128, Springer, 2022.
@inbook{jubelin2022circulating,
title = {Circulating Tumor Cells and ctDNA in Sarcomas},
author = {Camille Jubelin and Denis Cochonneau and Emilie Moranton and Javier Munoz-Garcia and Dominique Heymann},
editor = {Stanley P. Leong and S. David Nathanson and Jonathan S. Zager},
doi = {10.1007/978-3-030-93084-4_12},
year = {2022},
date = {2022-06-25},
urldate = {2022-06-25},
booktitle = {Cancer Metastasis Through the Lymphovascular System},
pages = {121--128},
publisher = {Springer},
abstract = {Sarcomas are clustered in two oncological entities named bone and soft tissue sarcomas. Both are rare cancers originating from the mesenchyme, characterized by their propensity to induce the development of lung metastases. Sarcoma cells escaping from the primary tumor site spread to the pulmonary tissue through the bloodstream where they found a favorable microenvironment to establish metastatic foci. The low number of patients, the high histological, genetic, and molecular heterogeneity of sarcomas combined with the absence of specific markers expressed by cancer cells make the detection and follow-up of the minimal residual disease challenging. Over the last decade, tremendous technological progress has been made towards the detection of recurrent diseases. The literature is now enriched of information describing the use of liquid biopsies in clinical care of sarcoma patients. This chapter aims to give a brief overview of the most recent data available on the detection of circulating tumor cells and circulating tumor DNA in sarcomas.},
keywords = {},
pubstate = {published},
tppubtype = {inbook}
}
Sarcomas are clustered in two oncological entities named bone and soft tissue sarcomas. Both are rare cancers originating from the mesenchyme, characterized by their propensity to induce the development of lung metastases. Sarcoma cells escaping from the primary tumor site spread to the pulmonary tissue through the bloodstream where they found a favorable microenvironment to establish metastatic foci. The low number of patients, the high histological, genetic, and molecular heterogeneity of sarcomas combined with the absence of specific markers expressed by cancer cells make the detection and follow-up of the minimal residual disease challenging. Over the last decade, tremendous technological progress has been made towards the detection of recurrent diseases. The literature is now enriched of information describing the use of liquid biopsies in clinical care of sarcoma patients. This chapter aims to give a brief overview of the most recent data available on the detection of circulating tumor cells and circulating tumor DNA in sarcomas.
de Cordoba, Borja Ruiz-Fernandez; Moreno, Haritz; Valencia, Karmele; Perurena, Naiara; Ruedas, Pablo; Walle, Thomas; Pezonaga-Torres, Alberto; Hinojosa, Juan; Guruceaga, Elisabet; Pineda-Lucena, Antonio; Abengozar-Muela, Marta; Cochonneau, Denis; Zandueta, Carolina; Martinez-Canarias, Susana; Teijeira, Alvaro; Ajona, Daniel; Ortiz-Espinosa, Sergio; Morales, Xabier; de Solorzano, Carlos Ortiz; Santisteban, Marta; Ramos-Garcia, Luis I; Guembe, Laura; Strnad, Vratislav; Heymann, Dominique; Hervas-Stubbs, Sandra; Pio, Ruben; Rodriguez-Ruiz, Maria E; de Andrea, Carlos E; Vicent, Silvestre; Melero, Ignacio; Lecanda, Fernando; Martinez-Monge, Rafael
Tumor ENPP1(CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer Article de journal
Dans: Cancer Discov, vol. 12, no. 5, p. 1356-1377, 2022, ISSN: 2159-8290.
@article{pmid35086922,
title = {Tumor ENPP1(CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer},
author = {Borja Ruiz-Fernandez de Cordoba and Haritz Moreno and Karmele Valencia and Naiara Perurena and Pablo Ruedas and Thomas Walle and Alberto Pezonaga-Torres and Juan Hinojosa and Elisabet Guruceaga and Antonio Pineda-Lucena and Marta Abengozar-Muela and Denis Cochonneau and Carolina Zandueta and Susana Martinez-Canarias and Alvaro Teijeira and Daniel Ajona and Sergio Ortiz-Espinosa and Xabier Morales and Carlos Ortiz de Solorzano and Marta Santisteban and Luis I Ramos-Garcia and Laura Guembe and Vratislav Strnad and Dominique Heymann and Sandra Hervas-Stubbs and Ruben Pio and Maria E Rodriguez-Ruiz and Carlos E de Andrea and Silvestre Vicent and Ignacio Melero and Fernando Lecanda and Rafael Martinez-Monge},
url = {https://pubmed.ncbi.nlm.nih.gov/35086922/},
doi = {10.1158/2159-8290.CD-21-0932},
issn = {2159-8290},
year = {2022},
date = {2022-05-01},
urldate = {2022-05-01},
journal = {Cancer Discov},
volume = {12},
number = {5},
pages = {1356-1377},
abstract = {Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF. Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF. Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
Muñoz-Garcia, Javier; Vargas-Franco, Jorge William; Royer, Bénédicte Brounais-Le; Cochonneau, Denis; Amiaud, Jérôme; Heymann, Marie-Françoise; Heymann, Dominique; Lézot, Frédéric
Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma Article de journal
Dans: Cancers, vol. 14, no. 7, p. 1765, 2022, ISSN: 2072-6694.
@article{cancers14071765,
title = {Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma},
author = {Javier Muñoz-Garcia and Jorge William Vargas-Franco and Bénédicte Brounais-Le Royer and Denis Cochonneau and Jérôme Amiaud and Marie-Françoise Heymann and Dominique Heymann and Frédéric Lézot},
url = {https://www.mdpi.com/2072-6694/14/7/1765},
doi = {10.3390/cancers14071765},
issn = {2072-6694},
year = {2022},
date = {2022-03-30},
urldate = {2022-01-01},
journal = {Cancers},
volume = {14},
number = {7},
pages = {1765},
abstract = {Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.
Jubelin, Camille; Munoz-Garcia, Javier; Cochonneau, Denis; Moranton, Emilie; Heymann, Marie Françoise; Heymann, Dominique
Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma Article de journal
Dans: Cancer Drug Resistance, vol. 5, iss. 5, p. 184-198, 2022.
@article{jubelin2022biological,
title = {Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma},
author = {Camille Jubelin and Javier Munoz-Garcia and Denis Cochonneau and Emilie Moranton and Marie Françoise Heymann and Dominique Heymann},
doi = {10.20517/cdr.2021.130},
year = {2022},
date = {2022-02-16},
urldate = {2022-02-16},
journal = {Cancer Drug Resistance},
volume = {5},
issue = {5},
pages = {184-198},
abstract = {Sarcomas are a large family of cancers originating in the mesenchyme. Composed of more than 100 histological subtypes, soft tissue and bone sarcomas remain clinically challenging, particularly in children and adolescents in whom sarcomas are the second most common malignant entities. Osteosarcoma is the main primary bone tumor in adolescents and young adults and is characterized by a high propensity to induce distant metastatic foci and become multi-drug resistant. The innate and acquired resistance of osteosarcoma can be explained by high histological heterogeneity and genetic/molecular diversity. In the last decade, the notion of cancer stem-like cells (CSCs) has emerged. This subset of cancer cells has been linked to drug resistance properties, recurrence of the disease, and therapeutic failure. Although CSCs remain controversial, many elements are in favor of them playing a role in the development of the drug resistance profile. The present review gives a brief overview of the most recent biological evidence of the presence of CSCs in osteosarcomas and their role in the drug resistance profile of these rare oncological entities. Their use as promising therapeutic targets is discussed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sarcomas are a large family of cancers originating in the mesenchyme. Composed of more than 100 histological subtypes, soft tissue and bone sarcomas remain clinically challenging, particularly in children and adolescents in whom sarcomas are the second most common malignant entities. Osteosarcoma is the main primary bone tumor in adolescents and young adults and is characterized by a high propensity to induce distant metastatic foci and become multi-drug resistant. The innate and acquired resistance of osteosarcoma can be explained by high histological heterogeneity and genetic/molecular diversity. In the last decade, the notion of cancer stem-like cells (CSCs) has emerged. This subset of cancer cells has been linked to drug resistance properties, recurrence of the disease, and therapeutic failure. Although CSCs remain controversial, many elements are in favor of them playing a role in the development of the drug resistance profile. The present review gives a brief overview of the most recent biological evidence of the presence of CSCs in osteosarcomas and their role in the drug resistance profile of these rare oncological entities. Their use as promising therapeutic targets is discussed.
Cadé, Marie; Muñoz-Garcia, Javier; Babuty, Antoine; Paré, Louis; Cochonneau, Denis; Fekir, Karim; Chatelais, Mathias; Heymann, Marie-Françoise; Lokajczyk, Anna; Boisson-Vidal, Catherine; Heymann, Dominique
FVIII regulates the molecular profile of endothelial cells: functional impact on the blood barrier and macrophage behavior Article de journal
Dans: Cell Mol Life Sci, vol. 79, no. 3, p. 145, 2022, ISSN: 1420-9071.
@article{pmid35190870,
title = {FVIII regulates the molecular profile of endothelial cells: functional impact on the blood barrier and macrophage behavior},
author = {Marie Cadé and Javier Muñoz-Garcia and Antoine Babuty and Louis Paré and Denis Cochonneau and Karim Fekir and Mathias Chatelais and Marie-Françoise Heymann and Anna Lokajczyk and Catherine Boisson-Vidal and Dominique Heymann},
doi = {10.1007/s00018-022-04178-5},
issn = {1420-9071},
year = {2022},
date = {2022-02-01},
urldate = {2022-02-01},
journal = {Cell Mol Life Sci},
volume = {79},
number = {3},
pages = {145},
abstract = {Hemophilia A is an inherited X-linked recessive bleeding disorder caused by deficient activity of blood coagulation factor VIII (FVIII). In addition, hemophilia patients show associated diseases including osteopenia, altered inflammation and vascular fragility which may represent the consequence of recurrent bleeding or may be related to the direct FVIII deficiency. Nowadays, recombinant FVIII is proposed to treat hemophilia patients with no circulating FVIII inhibitor. Initially described as a coenzyme to factor IXa for initiating thrombin generation, there is emerging evidence that FVIII is involved in multiple biological systems, including bone, vascular and immune systems. The present study investigated: (i) the functional activities of recombinant human FVIII (rFVIII) on endothelial cells, and (ii) the impact of rFVIII activities on the functional interactions of human monocytes and endothelial cells. We then investigated whether rFVIII had a direct effect on the adhesion of monocytes to the endothelium under physiological flow conditions. We observed that direct biological activities for rFVIII in endothelial cells were characterized by: (i) a decrease in endothelial cell adhesion to the underlying extracellular matrix; (ii) regulation of the transcriptomic and protein profiles of endothelial cells; (iii) an increase in the vascular tubes formed and vascular permeability in vitro; and (iv) an increase in monocyte adhesion activated endothelium and transendothelial migration. By regulating vascular permeability plus leukocyte adhesion and transendothelial migration, the present work highlights new biological functions for FVIII.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hemophilia A is an inherited X-linked recessive bleeding disorder caused by deficient activity of blood coagulation factor VIII (FVIII). In addition, hemophilia patients show associated diseases including osteopenia, altered inflammation and vascular fragility which may represent the consequence of recurrent bleeding or may be related to the direct FVIII deficiency. Nowadays, recombinant FVIII is proposed to treat hemophilia patients with no circulating FVIII inhibitor. Initially described as a coenzyme to factor IXa for initiating thrombin generation, there is emerging evidence that FVIII is involved in multiple biological systems, including bone, vascular and immune systems. The present study investigated: (i) the functional activities of recombinant human FVIII (rFVIII) on endothelial cells, and (ii) the impact of rFVIII activities on the functional interactions of human monocytes and endothelial cells. We then investigated whether rFVIII had a direct effect on the adhesion of monocytes to the endothelium under physiological flow conditions. We observed that direct biological activities for rFVIII in endothelial cells were characterized by: (i) a decrease in endothelial cell adhesion to the underlying extracellular matrix; (ii) regulation of the transcriptomic and protein profiles of endothelial cells; (iii) an increase in the vascular tubes formed and vascular permeability in vitro; and (iv) an increase in monocyte adhesion activated endothelium and transendothelial migration. By regulating vascular permeability plus leukocyte adhesion and transendothelial migration, the present work highlights new biological functions for FVIII.
Colliec-Jouault, Sylvia; Sinquin, Corinne; Ratiskol, Jacqueline; Heymann, Dominique; Ruiz-Velasco, Carmen; Chesneau, Julie
Anti-metastatic marine bacterial exopolysaccharide derivative and uses thereof Patent
2022, (US Patent 11,219,638).
@patent{colliec2022anti,
title = {Anti-metastatic marine bacterial exopolysaccharide derivative and uses thereof},
author = {Sylvia Colliec-Jouault and Corinne Sinquin and Jacqueline Ratiskol and Dominique Heymann and Carmen Ruiz-Velasco and Julie Chesneau},
url = {https://patents.google.com/patent/US11219638B2/en},
year = {2022},
date = {2022-01-11},
urldate = {2022-01-11},
publisher = {Google Patents},
abstract = {The invention provides a low-molecular-weight (15 kDa) over-sulfated exopolysaccharide (GYS15) prepared from a marine native exopolysaccharide excreted by a mesophilic marine bacterium from a deep-sea hydrothermal environment, and relates to the use of this low-molecular-weight over-sulfated exopolysaccharide for the prevention or inhibition of metastases formation.},
note = {US Patent 11,219,638},
keywords = {},
pubstate = {published},
tppubtype = {patent}
}
The invention provides a low-molecular-weight (15 kDa) over-sulfated exopolysaccharide (GYS15) prepared from a marine native exopolysaccharide excreted by a mesophilic marine bacterium from a deep-sea hydrothermal environment, and relates to the use of this low-molecular-weight over-sulfated exopolysaccharide for the prevention or inhibition of metastases formation.
1 publication
Muñoz-Garcia, Javier; Cochonneau, Denis; Télétchéa, Stéphane; Moranton, Emilie; Lanoe, Didier; Brion, Régis; Lézot, Frédéric; Heymann, Marie-Françoise; Heymann, Dominique
The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis Article de journal
Dans: Theranostics, vol. 11, no. 4, p. 1568–1593, 2021, ISSN: 1838-7640.
@article{pmid33408768,
title = {The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis},
author = {Javier Muñoz-Garcia and Denis Cochonneau and Stéphane Télétchéa and Emilie Moranton and Didier Lanoe and Régis Brion and Frédéric Lézot and Marie-Françoise Heymann and Dominique Heymann},
doi = {10.7150/thno.50683},
issn = {1838-7640},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Theranostics},
volume = {11},
number = {4},
pages = {1568--1593},
abstract = {Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.
2 publications
Ségaliny, Aude I; Brion, Régis; Brulin, Bénédicte; Maillasson, Mike; Charrier, Céline; Téletchéa, Stéphane; Heymann, Dominique
IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization Article de journal
Dans: Cytokine, vol. 76, no. 2, p. 170–181, 2015, ISSN: 10960023.
@article{Segaliny2015,
title = {IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization},
author = {Aude I Ségaliny and Régis Brion and Bénédicte Brulin and Mike Maillasson and Céline Charrier and Stéphane Téletchéa and Dominique Heymann},
doi = {10.1016/j.cyto.2015.05.029},
issn = {10960023},
year = {2015},
date = {2015-01-01},
journal = {Cytokine},
volume = {76},
number = {2},
pages = {170--181},
abstract = {Interleukin-34 (IL-34) is a newly-discovered homodimeric cytokine that regulates, like Macrophage Colony-Stimulating Factor (M-CSF), the differentiation of the myeloid lineage through M-CSF receptor (M-CSFR) signaling pathways. To date, both cytokines have been considered as competitive cytokines with regard to the M-CSFR. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the M-CSFR. We demonstrate that simultaneous addition of M-CSF and IL-34 led to a specific activation pattern on the M-CSFR, with higher phosphorylation of the tyrosine residues at low concentrations. Similarly, both cytokines showed an additive effect on cellular proliferation or viability. In addition, BIAcore experiments demonstrated that M-CSF binds to IL-34, and molecular docking studies predicted the formation of a heteromeric M-CSF/IL-34 cytokine. A proximity ligation assay confirmed this interaction between the cytokines. Finally, co-expression of the M-CSFR and its ligands differentially regulated M-CSFR trafficking into the cell. This study establishes a new foundation for the understanding of the functional relationship between IL-34 and M-CSF, and gives a new vision for the development of therapeutic approaches targeting the IL-34/M-CSF/M-CSFR axis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Interleukin-34 (IL-34) is a newly-discovered homodimeric cytokine that regulates, like Macrophage Colony-Stimulating Factor (M-CSF), the differentiation of the myeloid lineage through M-CSF receptor (M-CSFR) signaling pathways. To date, both cytokines have been considered as competitive cytokines with regard to the M-CSFR. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the M-CSFR. We demonstrate that simultaneous addition of M-CSF and IL-34 led to a specific activation pattern on the M-CSFR, with higher phosphorylation of the tyrosine residues at low concentrations. Similarly, both cytokines showed an additive effect on cellular proliferation or viability. In addition, BIAcore experiments demonstrated that M-CSF binds to IL-34, and molecular docking studies predicted the formation of a heteromeric M-CSF/IL-34 cytokine. A proximity ligation assay confirmed this interaction between the cytokines. Finally, co-expression of the M-CSFR and its ligands differentially regulated M-CSFR trafficking into the cell. This study establishes a new foundation for the understanding of the functional relationship between IL-34 and M-CSF, and gives a new vision for the development of therapeutic approaches targeting the IL-34/M-CSF/M-CSFR axis.
Faucon, Adrien; Benhelli-Mokrani, Houda; w Córdova, Luis A; Brulin, Bénédicte; Heymann, Dominique; Hulin, Philippe; Nedellec, Steven; Ishow, Eléna
Are Fluorescent Organic Nanoparticles Relevant Tools for Tracking Cancer Cells or Macrophages? Article de journal
Dans: Advanced Healthcare Materials, vol. 4, no. 17, p. 2727–2734, 2015, ISSN: 21922659.
@article{Faucon2015,
title = {Are Fluorescent Organic Nanoparticles Relevant Tools for Tracking Cancer Cells or Macrophages?},
author = {Adrien Faucon and Houda Benhelli-Mokrani and Luis A w Córdova and Bénédicte Brulin and Dominique Heymann and Philippe Hulin and Steven Nedellec and Eléna Ishow},
doi = {10.1002/adhm.201500562},
issn = {21922659},
year = {2015},
date = {2015-01-01},
journal = {Advanced Healthcare Materials},
volume = {4},
number = {17},
pages = {2727--2734},
abstract = {Strongly solvatochromic fluorophores are devised, containing alkyl chains and enable to self-assemble as very bright fluorescent organic nanoparticles (FONs) in water (φf = 0.28). The alkyl chains impart each fluorophore with strongly hydrophobic surroundings, causing distinct emission colors between FONs where the fluorophores are associated, and their disassembled state. Such color change is harnessed to assess the long-term fate of FONs in both cancer cells and monocytes/macrophages. Disintegration of the orange-emitting FONs by monocytes/macrophages is evidenced through the formation of micrometer green-yellowish emitting vesicles. By contrast, cancer cells retain longer the integrity of organic nanoparticles. In both cases, no significant toxicity is detected, making FONs as valuable bioimaging agents for cell tracking with weak risks of deleterious accumulation and low degradation rate. Long-term fate of fluorescent organic nanoparticles (FONs), known as very bright imaging agents and made of self-assembled solvatochromic fluorophores, is explored in both cancer cells and monocytes/macrophages. Disintegration of the orange-emitting FONs by monocytes/macrophages is evidenced through the formation of micrometer green-yellowish emitting vesicles. By contrast, cancer cells retain longer the integrity of organic nanoparticles.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Strongly solvatochromic fluorophores are devised, containing alkyl chains and enable to self-assemble as very bright fluorescent organic nanoparticles (FONs) in water (φf = 0.28). The alkyl chains impart each fluorophore with strongly hydrophobic surroundings, causing distinct emission colors between FONs where the fluorophores are associated, and their disassembled state. Such color change is harnessed to assess the long-term fate of FONs in both cancer cells and monocytes/macrophages. Disintegration of the orange-emitting FONs by monocytes/macrophages is evidenced through the formation of micrometer green-yellowish emitting vesicles. By contrast, cancer cells retain longer the integrity of organic nanoparticles. In both cases, no significant toxicity is detected, making FONs as valuable bioimaging agents for cell tracking with weak risks of deleterious accumulation and low degradation rate. Long-term fate of fluorescent organic nanoparticles (FONs), known as very bright imaging agents and made of self-assembled solvatochromic fluorophores, is explored in both cancer cells and monocytes/macrophages. Disintegration of the orange-emitting FONs by monocytes/macrophages is evidenced through the formation of micrometer green-yellowish emitting vesicles. By contrast, cancer cells retain longer the integrity of organic nanoparticles.
2022
Cadé, Marie; Muñoz-Garcia, Javier; Babuty, Antoine; Fouassier, Marc; Heymann, Marie-Francoise; Monahan, Paul E; Heymann, Dominique
FVIII at the crossroad of coagulation, bone and immune biology: Emerging evidence of biological activities beyond hemostasis Article de journal
Dans: Drug Discov Today, vol. 27, no. 1, p. 102–116, 2022, ISSN: 1878-5832.
@article{pmid34311113,
title = {FVIII at the crossroad of coagulation, bone and immune biology: Emerging evidence of biological activities beyond hemostasis},
author = {Marie Cadé and Javier Muñoz-Garcia and Antoine Babuty and Marc Fouassier and Marie-Francoise Heymann and Paul E Monahan and Dominique Heymann},
doi = {10.1016/j.drudis.2021.07.015},
issn = {1878-5832},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Drug Discov Today},
volume = {27},
number = {1},
pages = {102--116},
abstract = {Hemophilia A is an X-linked hereditary disorder that results from deficient coagulation factor VIII (FVIII) activity, leading to spontaneous bleeding episodes, particularly in joints and muscles. FVIII deficiency has been associated with altered bone remodeling, dysregulated macrophage polarization, and inflammatory processes that are associated with the neoformation of abnormal blood vessels. Treatment based on FVIII replacement can lead to the development of inhibitors that render FVIII concentrate infusion ineffective. In this context, hemophilia has entered a new therapeutic era with the development of new drugs, such as emicizumab, that seek to restore the hemostatic balance by bypassing pathologically acquired antibodies. We discuss the potential extrahemostatic functions of FVIII that may be crucial for defining future therapies in hemophilia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hemophilia A is an X-linked hereditary disorder that results from deficient coagulation factor VIII (FVIII) activity, leading to spontaneous bleeding episodes, particularly in joints and muscles. FVIII deficiency has been associated with altered bone remodeling, dysregulated macrophage polarization, and inflammatory processes that are associated with the neoformation of abnormal blood vessels. Treatment based on FVIII replacement can lead to the development of inhibitors that render FVIII concentrate infusion ineffective. In this context, hemophilia has entered a new therapeutic era with the development of new drugs, such as emicizumab, that seek to restore the hemostatic balance by bypassing pathologically acquired antibodies. We discuss the potential extrahemostatic functions of FVIII that may be crucial for defining future therapies in hemophilia.
Rabé, Marion; Fonteneau, Lucie; Oliver, Lisa; Morales-Molina, Alvaro; Jubelin, Camille; Garcia-Castro, Javier; Heymann, Dominique; Gratas, Catherine; Vallette, François M
Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment Article de journal
Dans: Frontiers in Cell and Developmental Biology, vol. 10, p. 975, 2022.
@article{rabe2022cellular,
title = {Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment},
author = {Marion Rabé and Lucie Fonteneau and Lisa Oliver and Alvaro Morales-Molina and Camille Jubelin and Javier Garcia-Castro and Dominique Heymann and Catherine Gratas and François M Vallette},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Frontiers in Cell and Developmental Biology},
volume = {10},
pages = {975},
publisher = {Frontiers},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2021
Avnet, Sofia; Lemma, Silvia; Cortini, Margherita; Pompo, Gemma Di; Perut, Francesca; Lipreri, Maria Veronica; Roncuzzi, Laura; Columbaro, Marta; Errani, Costantino; Longhi, Alessandra; Zini, Nicoletta; Heymann, Dominique; Dominici, Massimo; Grisendi, Giulia; Golinelli, Giulia; Consolino, Lorena; Longo, Dario Livio; Nanni, Cristina; Righi, Alberto; Baldini, Nicola
The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma Article de journal
Dans: Cancers (Basel), vol. 13, no. 22, 2021, ISSN: 2072-6694.
@article{pmid34831016,
title = {The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma},
author = {Sofia Avnet and Silvia Lemma and Margherita Cortini and Gemma Di Pompo and Francesca Perut and Maria Veronica Lipreri and Laura Roncuzzi and Marta Columbaro and Costantino Errani and Alessandra Longhi and Nicoletta Zini and Dominique Heymann and Massimo Dominici and Giulia Grisendi and Giulia Golinelli and Lorena Consolino and Dario Livio Longo and Cristina Nanni and Alberto Righi and Nicola Baldini},
doi = {10.3390/cancers13225855},
issn = {2072-6694},
year = {2021},
date = {2021-11-01},
urldate = {2021-11-01},
journal = {Cancers (Basel)},
volume = {13},
number = {22},
abstract = {Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.
Muñoz-Garcia, Javier; Jubelin, Camille; Loussouarn, Aurélie; Goumard, Matisse; Griscom, Laurent; Renodon-Cornière, Axelle; Heymann, Marie-Françoise; Heymann, Dominique
In vitro three-dimensional cell cultures for bone sarcomas Article de journal
Dans: Journal of Bone Oncology, vol. 30, p. 100379, 2021, ISSN: 2212-1374.
@article{munoz2021vitro,
title = {In vitro three-dimensional cell cultures for bone sarcomas},
author = {Javier Muñoz-Garcia and Camille Jubelin and Aurélie Loussouarn and Matisse Goumard and Laurent Griscom and Axelle Renodon-Cornière and Marie-Françoise Heymann and Dominique Heymann},
editor = {Elsevier},
doi = {10.1016/j.jbo.2021.100379},
issn = {2212-1374},
year = {2021},
date = {2021-10-01},
urldate = {2021-10-01},
journal = {Journal of Bone Oncology},
volume = {30},
pages = {100379},
publisher = {Elsevier},
abstract = {Bone sarcomas are rare tumour entities that arise from the mesenchyme most of which are highly heterogeneous at the cellular, genetic and epigenetic levels. The three main types are osteosarcoma, Ewing sarcoma, and chondrosarcoma. These oncological entities are characterised by high morbidity and mortality and an absence of significant therapeutic improvement in the last four decades. In the field of oncology, in vitro cultures of cancer cells have been extensively used for drug screening unfortunately with limited success. Indeed, despite the massive knowledge acquired from conventional 2D culture methods, scientific community has been challenged by the loss of efficacy of drugs when moved to clinical trials. The recent explosion of new 3D culture methods is paving the way to more relevant in vitro models mimicking the in vivo tumour environment (e.g. bone structure) with biological responses close to the in vivo context. The present review gives a brief overview of the latest advances of the 3D culture methods used for studying primary bone sarcomas.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Bone sarcomas are rare tumour entities that arise from the mesenchyme most of which are highly heterogeneous at the cellular, genetic and epigenetic levels. The three main types are osteosarcoma, Ewing sarcoma, and chondrosarcoma. These oncological entities are characterised by high morbidity and mortality and an absence of significant therapeutic improvement in the last four decades. In the field of oncology, in vitro cultures of cancer cells have been extensively used for drug screening unfortunately with limited success. Indeed, despite the massive knowledge acquired from conventional 2D culture methods, scientific community has been challenged by the loss of efficacy of drugs when moved to clinical trials. The recent explosion of new 3D culture methods is paving the way to more relevant in vitro models mimicking the in vivo tumour environment (e.g. bone structure) with biological responses close to the in vivo context. The present review gives a brief overview of the latest advances of the 3D culture methods used for studying primary bone sarcomas.
Danieau, Geoffroy; Morice, Sarah; Renault, Sarah; Brion, Régis; Biteau, Kevin; Amiaud, Jérôme; Cadé, Marie; Heymann, Dominique; Lézot, Frédéric; Verrecchia, Franck; Rédini, Françoise; Royer, Bénédicte Brounais-Le
Dans: Pharmaceuticals (Basel), vol. 14, no. 5, 2021, ISSN: 1424-8247.
@article{pmid34062831,
title = {ICG-001, an Inhibitor of the β-Catenin and cAMP Response Element-Binding Protein Dependent Gene Transcription, Decreases Proliferation but Enhances Migration of Osteosarcoma Cells},
author = {Geoffroy Danieau and Sarah Morice and Sarah Renault and Régis Brion and Kevin Biteau and Jérôme Amiaud and Marie Cadé and Dominique Heymann and Frédéric Lézot and Franck Verrecchia and Françoise Rédini and Bénédicte Brounais-Le Royer},
doi = {10.3390/ph14050421},
issn = {1424-8247},
year = {2021},
date = {2021-05-01},
urldate = {2021-05-01},
journal = {Pharmaceuticals (Basel)},
volume = {14},
number = {5},
abstract = {High-grade osteosarcomas are the most frequent malignant bone tumors in the pediatric population, with 150 patients diagnosed every year in France. Osteosarcomas are associated with low survival rates for high risk patients (metastatic and relapsed diseases). Knowing that the canonical Wnt signaling pathway (Wnt/β-catenin) plays a complex but a key role in primary and metastatic development of osteosarcoma, the aim of this work was to analyze the effects of ICG-001, a CBP/β-catenin inhibitor blocking the β-catenin dependent gene transcription, in three human osteosarcoma cell lines (KHOS, MG63 and 143B). The cell proliferation and migration were first evaluated in vitro after ICG-001 treatment. Secondly, a mouse model of osteosarcoma was used to establish the in vivo biological effect of ICG-001 on osteosarcoma growth and metastatic dissemination. In vitro, ICG-001 treatment strongly inhibits osteosarcoma cell proliferation through a cell cycle blockade in the G0/G1 phase, but surprisingly, increases cell migration of the three cell lines. Moreover, ICG-001 does not modulate tumor growth in the osteosarcoma mouse model but, rather significantly increases the metastatic dissemination to lungs. Taken together, these results highlight, despite an anti-proliferative effect, a deleterious pro-migratory role of ICG-001 in osteosarcoma.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
High-grade osteosarcomas are the most frequent malignant bone tumors in the pediatric population, with 150 patients diagnosed every year in France. Osteosarcomas are associated with low survival rates for high risk patients (metastatic and relapsed diseases). Knowing that the canonical Wnt signaling pathway (Wnt/β-catenin) plays a complex but a key role in primary and metastatic development of osteosarcoma, the aim of this work was to analyze the effects of ICG-001, a CBP/β-catenin inhibitor blocking the β-catenin dependent gene transcription, in three human osteosarcoma cell lines (KHOS, MG63 and 143B). The cell proliferation and migration were first evaluated in vitro after ICG-001 treatment. Secondly, a mouse model of osteosarcoma was used to establish the in vivo biological effect of ICG-001 on osteosarcoma growth and metastatic dissemination. In vitro, ICG-001 treatment strongly inhibits osteosarcoma cell proliferation through a cell cycle blockade in the G0/G1 phase, but surprisingly, increases cell migration of the three cell lines. Moreover, ICG-001 does not modulate tumor growth in the osteosarcoma mouse model but, rather significantly increases the metastatic dissemination to lungs. Taken together, these results highlight, despite an anti-proliferative effect, a deleterious pro-migratory role of ICG-001 in osteosarcoma.
Muñoz-Garcia, Javier; Mazza, Mattia; Alliot, Cyrille; Sinquin, Corinne; Colliec-Jouault, Sylvia; Heymann, Dominique; Huclier-Markai, Sandrine
Antiproliferative Properties of Scandium Exopolysaccharide Complexes on Several Cancer Cell Lines Article de journal
Dans: Mar Drugs, vol. 19, no. 3, 2021, ISSN: 1660-3397.
@article{pmid33806830,
title = {Antiproliferative Properties of Scandium Exopolysaccharide Complexes on Several Cancer Cell Lines},
author = {Javier Muñoz-Garcia and Mattia Mazza and Cyrille Alliot and Corinne Sinquin and Sylvia Colliec-Jouault and Dominique Heymann and Sandrine Huclier-Markai},
doi = {10.3390/md19030174},
issn = {1660-3397},
year = {2021},
date = {2021-03-01},
urldate = {2021-03-01},
journal = {Mar Drugs},
volume = {19},
number = {3},
abstract = {Antimetastatic properties on both murine and human osteosarcoma cell lines (POS-1 and KHOS) have been evidenced using exopolysaccharide (EPS) derivatives, produced by bacterium. These derivatives had no significant effect on the cell cycle neither a pro-apoptotic effect on osteosarcoma cells. Based on this observation, these EPSs could be employed as new drug delivery systems for therapeutic uses. A theranostic approach, i.e., combination of a predictive biomarker with a therapeutic agent, has been developed notably by combining with true pair of theranostic radionuclides, such as scandium Sc/Sc. However, it is crucial to ensure that, once complexation is done, the biological properties of the vector remain intact, allowing the molecular tropism of the ligand to recognize its molecular target. It is important to assess if the biological properties of EPS evidenced on osteosarcoma cell lines remain when scandium is complexed to the polymers and can be extended to other cancer cell types. Scandium-EPS complexes were thus tested in vitro on human cell lines: MNNG/HOS osteosarcoma, A375 melanoma, A549 lung adenocarcinoma, U251 glioma, MDA231 breast cancer, and Caco2 colon cancer cells. An xCELLigence Real Cell Time Analysis (RTCA) technology assay was used to monitor for 160 h, the proliferation kinetics of the different cell lines. The tested complexes exhibited an anti-proliferative effect, this effect was more effective compared to EPS alone. This increase of the antiproliferative properties was explained by a change in conformation of EPS complexes due to their polyelectrolyte nature that was induced by complexation. Alterations of both growth factor-receptor signaling, and transmembrane protein interactions could be the principal cause of the antiproliferative effect. These results are very promising and reveal that EPS can be coupled to scandium for improving its biological effects and also suggesting that no major structural modification occurs on the ligand.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Antimetastatic properties on both murine and human osteosarcoma cell lines (POS-1 and KHOS) have been evidenced using exopolysaccharide (EPS) derivatives, produced by bacterium. These derivatives had no significant effect on the cell cycle neither a pro-apoptotic effect on osteosarcoma cells. Based on this observation, these EPSs could be employed as new drug delivery systems for therapeutic uses. A theranostic approach, i.e., combination of a predictive biomarker with a therapeutic agent, has been developed notably by combining with true pair of theranostic radionuclides, such as scandium Sc/Sc. However, it is crucial to ensure that, once complexation is done, the biological properties of the vector remain intact, allowing the molecular tropism of the ligand to recognize its molecular target. It is important to assess if the biological properties of EPS evidenced on osteosarcoma cell lines remain when scandium is complexed to the polymers and can be extended to other cancer cell types. Scandium-EPS complexes were thus tested in vitro on human cell lines: MNNG/HOS osteosarcoma, A375 melanoma, A549 lung adenocarcinoma, U251 glioma, MDA231 breast cancer, and Caco2 colon cancer cells. An xCELLigence Real Cell Time Analysis (RTCA) technology assay was used to monitor for 160 h, the proliferation kinetics of the different cell lines. The tested complexes exhibited an anti-proliferative effect, this effect was more effective compared to EPS alone. This increase of the antiproliferative properties was explained by a change in conformation of EPS complexes due to their polyelectrolyte nature that was induced by complexation. Alterations of both growth factor-receptor signaling, and transmembrane protein interactions could be the principal cause of the antiproliferative effect. These results are very promising and reveal that EPS can be coupled to scandium for improving its biological effects and also suggesting that no major structural modification occurs on the ligand.
Heymann, Marie-Françoise; Schiavone, Kristina; Heymann, Dominique
Bone sarcomas in the immunotherapy era Article de journal
Dans: Br J Pharmacol, vol. 178, no. 9, p. 1955–1972, 2021, ISSN: 1476-5381.
@article{pmid31975481,
title = {Bone sarcomas in the immunotherapy era},
author = {Marie-Françoise Heymann and Kristina Schiavone and Dominique Heymann},
doi = {10.1111/bph.14999},
issn = {1476-5381},
year = {2021},
date = {2021-01-23},
urldate = {2020-01-23},
journal = {Br J Pharmacol},
volume = {178},
number = {9},
pages = {1955--1972},
abstract = {Bone sarcomas are primary bone tumours found mainly in children and adolescents, as osteosarcoma and Ewing's sarcoma, and in adults in their 40s as chondrosarcoma. The last four decades the development of therapeutic approaches was based on drug combinations have shown no real improvement in overall survival. Recently oncoimmunology has allowed a better understand of the crucial role played by the immune system in the oncologic process. This led to clinical trials with the aim of reprogramming the immune system to facilitate cancer cell recognition. Immune infiltrates of bone sarcomas have been characterized and their molecular profiling identified as immune therapeutic targets. Unfortunately, the clinical responses in trials remain anecdotal but highlight the necessity to improve the characterization of tumour micro-environment to unlock the immunotherapeutic response, especially in their paediatric forms. Bone sarcomas have entered the immunotherapy era and here we overview the recent developments in immunotherapies in these sarcomas. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Bone sarcomas are primary bone tumours found mainly in children and adolescents, as osteosarcoma and Ewing's sarcoma, and in adults in their 40s as chondrosarcoma. The last four decades the development of therapeutic approaches was based on drug combinations have shown no real improvement in overall survival. Recently oncoimmunology has allowed a better understand of the crucial role played by the immune system in the oncologic process. This led to clinical trials with the aim of reprogramming the immune system to facilitate cancer cell recognition. Immune infiltrates of bone sarcomas have been characterized and their molecular profiling identified as immune therapeutic targets. Unfortunately, the clinical responses in trials remain anecdotal but highlight the necessity to improve the characterization of tumour micro-environment to unlock the immunotherapeutic response, especially in their paediatric forms. Bone sarcomas have entered the immunotherapy era and here we overview the recent developments in immunotherapies in these sarcomas. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
Tabti, Redouane; Lamoureux, François; Charrier, Céline; Ory, Benjamin; Heymann, Dominique; Bentouhami, Embarek; Désaubry, Laurent
Development of prohibitin ligands against osteoporosis Article de journal
Dans: Eur J Med Chem, vol. 210, p. 112961, 2021, ISSN: 1768-3254.
@article{pmid33129591,
title = {Development of prohibitin ligands against osteoporosis},
author = {Redouane Tabti and François Lamoureux and Céline Charrier and Benjamin Ory and Dominique Heymann and Embarek Bentouhami and Laurent Désaubry},
doi = {10.1016/j.ejmech.2020.112961},
issn = {1768-3254},
year = {2021},
date = {2021-01-15},
urldate = {2021-01-01},
journal = {Eur J Med Chem},
volume = {210},
pages = {112961},
abstract = {Current therapeutic approaches to osteoporosis display some potential adverse effects and a limited efficacy on non-vertebral fracture reduction. Some sulfonylamidines targeting the scaffold proteins prohibitins-1 and 2 (PHB1/2) have been showed to inhibit the formation of osteoclasts in charge of bone resorption. Herein, we report the development of a second generation of anti-osteoclastic PHB ligands. The most potent compound, IN45, showed 88% inhibition at the low concentration of 5 μM, indicates that it might serve as a basis for the development of new antiosteoporotic drugs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Current therapeutic approaches to osteoporosis display some potential adverse effects and a limited efficacy on non-vertebral fracture reduction. Some sulfonylamidines targeting the scaffold proteins prohibitins-1 and 2 (PHB1/2) have been showed to inhibit the formation of osteoclasts in charge of bone resorption. Herein, we report the development of a second generation of anti-osteoclastic PHB ligands. The most potent compound, IN45, showed 88% inhibition at the low concentration of 5 μM, indicates that it might serve as a basis for the development of new antiosteoporotic drugs.
Heymann, Dominique
The Elderly and the COVID 19 Crisis: A Chronicle of Deaths Foretold, in Isolation and Total Indifference Article de journal
Dans: Front Public Health, vol. 8, p. 602982, 2021, ISSN: 2296-2565.
@article{pmid33490021,
title = {The Elderly and the COVID 19 Crisis: A Chronicle of Deaths Foretold, in Isolation and Total Indifference},
author = {Dominique Heymann},
doi = {10.3389/fpubh.2020.602982},
issn = {2296-2565},
year = {2021},
date = {2021-01-08},
urldate = {2021-01-08},
journal = {Front Public Health},
volume = {8},
pages = {602982},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Heymann, Clément J F; Bard, Jean-Marie; Heymann, Marie-Françoise; Heymann, Dominique; Bobin-Dubigeon, Christine
The intratumoral microbiome: Characterization methods and functional impact Article de journal
Dans: Cancer Lett, vol. 522, p. 63–79, 2021, ISSN: 1872-7980.
@article{pmid34517085,
title = {The intratumoral microbiome: Characterization methods and functional impact},
author = {Clément J F Heymann and Jean-Marie Bard and Marie-Françoise Heymann and Dominique Heymann and Christine Bobin-Dubigeon},
doi = {10.1016/j.canlet.2021.09.009},
issn = {1872-7980},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Cancer Lett},
volume = {522},
pages = {63--79},
abstract = {Live-pathogenic bacteria, which were identified inside tumors hundreds year ago, are key elements in modern cancer research. As they have a relatively accessible genome, they offer a multitude of metabolic engineering opportunities, useful in several clinical fields. Better understanding of the tumor microenvironment and its associated microbiome would help conceptualize new metabolically engineered species, triggering efficient therapeutic responses against cancer. Unfortunately, given the low microbial biomass nature of tumors, characterizing the tumor microbiome remains a challenge. Tumors have a high host versus bacterial DNA ratio, making it extremely complex to identify tumor-associated bacteria. Nevertheless, with the improvements in next-generation analytic tools, recent studies demonstrated the existence of intratumor bacteria inside defined tumors. It is now proven that each cancer subtype has a unique microbiome, characterized by bacterial communities with specific metabolic functions. This review provides a brief overview of the main approaches used to characterize the tumor microbiome, and of the recently proposed functions of intracellular bacteria identified in oncological entities. The therapeutic aspects of live-pathogenic microbes are also discussed, regarding the tumor microenvironment of each cancer type.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Live-pathogenic bacteria, which were identified inside tumors hundreds year ago, are key elements in modern cancer research. As they have a relatively accessible genome, they offer a multitude of metabolic engineering opportunities, useful in several clinical fields. Better understanding of the tumor microenvironment and its associated microbiome would help conceptualize new metabolically engineered species, triggering efficient therapeutic responses against cancer. Unfortunately, given the low microbial biomass nature of tumors, characterizing the tumor microbiome remains a challenge. Tumors have a high host versus bacterial DNA ratio, making it extremely complex to identify tumor-associated bacteria. Nevertheless, with the improvements in next-generation analytic tools, recent studies demonstrated the existence of intratumor bacteria inside defined tumors. It is now proven that each cancer subtype has a unique microbiome, characterized by bacterial communities with specific metabolic functions. This review provides a brief overview of the main approaches used to characterize the tumor microbiome, and of the recently proposed functions of intracellular bacteria identified in oncological entities. The therapeutic aspects of live-pathogenic microbes are also discussed, regarding the tumor microenvironment of each cancer type.
2020
Guyon, Nina; Garnier, Delphine; Briand, Joséphine; Nadaradjane, Arulraj; Bougras-Cartron, Gwenola; Raimbourg, Judith; Campone, Mario; Heymann, Dominique; Vallette, François M; Frenel, Jean-Sébastien; Cartron, Pierre-François
Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells Article de journal
Dans: Cell Death Dis, vol. 11, no. 12, p. 1048, 2020, ISSN: 2041-4889.
@article{pmid33311449,
title = {Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells},
author = {Nina Guyon and Delphine Garnier and Joséphine Briand and Arulraj Nadaradjane and Gwenola Bougras-Cartron and Judith Raimbourg and Mario Campone and Dominique Heymann and François M Vallette and Jean-Sébastien Frenel and Pierre-François Cartron},
doi = {10.1038/s41419-020-03224-z},
issn = {2041-4889},
year = {2020},
date = {2020-12-11},
urldate = {2020-12-11},
journal = {Cell Death Dis},
volume = {11},
number = {12},
pages = {1048},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Oliver, Lisa; Lalier, Lisenn; Salaud, Céline; Heymann, Dominique; Cartron, Pierre François; Vallette, François M
Drug resistance in glioblastoma: are persisters the key to therapy? Article de journal
Dans: Cancer Drug Resistance, vol. 3, no. 3, p. 287–301, 2020.
@article{oliver2020drug,
title = {Drug resistance in glioblastoma: are persisters the key to therapy?},
author = {Lisa Oliver and Lisenn Lalier and Céline Salaud and Dominique Heymann and Pierre François Cartron and François M Vallette},
doi = {10.20517/cdr.2020.29},
year = {2020},
date = {2020-08-07},
urldate = {2020-01-01},
journal = {Cancer Drug Resistance},
volume = {3},
number = {3},
pages = {287--301},
abstract = {Glioblastoma (GBM) represents the main form of brain tumors in adults, and one of the most aggressive cancers overall. The treatment of GBM is a combination of surgery (when possible), chemotherapy (usually Temozolomide, TMZ) and radiotherapy (RT). However, despite this heavy treatment, GBM invariably recur and the median length of survival following diagnosis is 12 to 15 months, with less than 10% of people surviving longer than five years. GBM is extremely resistant to most treatments because of its heterogeneous nature, which is associated with extreme clonal plasticity and the presence of cancer stem cells, refractory to TMZ- and RT-induced cell death. In this review, we explore the mechanisms by which cancer cells, and especially GBM, can acquire resistance to treatment. We describe and discuss the concept of persister/tolerant cells that precede and/or accompany the acquisition of resistance. Persister/tolerant cells are cancer cells that are not eliminated by treatment(s) because of different mechanisms ranging from dormancy/quiescence to senescence. We discuss the possibility of targeting these mechanisms in new therapeutic regimen.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Glioblastoma (GBM) represents the main form of brain tumors in adults, and one of the most aggressive cancers overall. The treatment of GBM is a combination of surgery (when possible), chemotherapy (usually Temozolomide, TMZ) and radiotherapy (RT). However, despite this heavy treatment, GBM invariably recur and the median length of survival following diagnosis is 12 to 15 months, with less than 10% of people surviving longer than five years. GBM is extremely resistant to most treatments because of its heterogeneous nature, which is associated with extreme clonal plasticity and the presence of cancer stem cells, refractory to TMZ- and RT-induced cell death. In this review, we explore the mechanisms by which cancer cells, and especially GBM, can acquire resistance to treatment. We describe and discuss the concept of persister/tolerant cells that precede and/or accompany the acquisition of resistance. Persister/tolerant cells are cancer cells that are not eliminated by treatment(s) because of different mechanisms ranging from dormancy/quiescence to senescence. We discuss the possibility of targeting these mechanisms in new therapeutic regimen.
Briand, Joséphine; Sérandour, Aurélien A; Nadaradjane, Arulraj; Bougras-Cartron, Gwenola; Heymann, Dominique; Ory, Benjamin; Vallette, François M; Cartron, Pierre-François
N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool Article de journal
Dans: Mol Ther Nucleic Acids, vol. 22, p. 72–83, 2020, ISSN: 2162-2531.
@article{pmid32916600,
title = {N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool},
author = {Joséphine Briand and Aurélien A Sérandour and Arulraj Nadaradjane and Gwenola Bougras-Cartron and Dominique Heymann and Benjamin Ory and François M Vallette and Pierre-François Cartron},
doi = {10.1016/j.omtn.2020.08.010},
issn = {2162-2531},
year = {2020},
date = {2020-08-01},
urldate = {2020-08-01},
journal = {Mol Ther Nucleic Acids},
volume = {22},
pages = {72--83},
abstract = {MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3' UTR duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3' UTR duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).
Briand, Joséphine; Sérandour, Aurélien A; Nadaradjane, Arulraj; Bougras-Cartron, Gwenola; Heymann, Dominique; Ory, Benjamin; Vallette, François M; Cartron, Pierre-François
N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool Article de journal
Dans: Mol Ther Nucleic Acids, vol. 22, p. 72–83, 2020, ISSN: 2162-2531.
@article{pmid32916600b,
title = {N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool},
author = {Joséphine Briand and Aurélien A Sérandour and Arulraj Nadaradjane and Gwenola Bougras-Cartron and Dominique Heymann and Benjamin Ory and François M Vallette and Pierre-François Cartron},
doi = {10.1016/j.omtn.2020.08.010},
issn = {2162-2531},
year = {2020},
date = {2020-08-01},
urldate = {2020-08-01},
journal = {Mol Ther Nucleic Acids},
volume = {22},
pages = {72--83},
abstract = {MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3' UTR duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3' UTR duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).
Heymann, Marie-Francoise; Lezot, Frederic; Heymann, Dominique
Bisphosphonates in common pediatric and adult bone sarcomas Article de journal
Dans: Bone, vol. 139, p. 115523, 2020, ISSN: 1873-2763.
@article{pmid32622877,
title = {Bisphosphonates in common pediatric and adult bone sarcomas},
author = {Marie-Francoise Heymann and Frederic Lezot and Dominique Heymann},
doi = {10.1016/j.bone.2020.115523},
issn = {1873-2763},
year = {2020},
date = {2020-07-03},
urldate = {2020-01-01},
journal = {Bone},
volume = {139},
pages = {115523},
abstract = {The therapeutic strategies proposed currently for bone sarcomas are based on neo-adjuvant chemotherapy, delayed en-bloc wide resection, and adjuvant chemotherapy. Unfortunately, bone sarcomas are characterized by high rates of poor drug response, with a high risk of drug resistance, local recurrence and/or a high propensity for induced metastases. The pathogenesis of bone sarcomas is strongly associated with dysregulation of local bone remodeling and increased osteolysis that plays a part in tumor development. In this context, bisphosphonates (BPs) have been proposed as a single agent or in combination with conventional drugs to block bone resorption and the vicious cycle established between bone and sarcoma cells. Pre-clinical in vitro studies revealed the potential "anti-tumor" activities of nitrogen-bisphosphonates (N-BPs). In pre-clinical models, N-BPs reduced significantly primary tumor growth in osteosarcoma and Ewing sarcoma, and the installation of lung metastases. In chondrosarcoma, N-BPs reduced the recurrence of local tumors after intralesional curettage, and increased overall survival. In pediatric and adult osteosarcoma patients, N-BPs have been assessed in combination with conventional chemotherapy and surgery in randomized phase 3 studies with no improvement in clinical outcome. The lack of benefit may potentially be explained by the biological impact of N-BPs on macrophage differentiation/recruitment which may alter CD8-T lymphocyte infiltration. Thanks to their considerable affinity for the mineralized extracellular matrix, BPs are an excellent platform for drug delivery in malignant bone sites with reduced systemic toxicity, which opens up new opportunities for their future use.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The therapeutic strategies proposed currently for bone sarcomas are based on neo-adjuvant chemotherapy, delayed en-bloc wide resection, and adjuvant chemotherapy. Unfortunately, bone sarcomas are characterized by high rates of poor drug response, with a high risk of drug resistance, local recurrence and/or a high propensity for induced metastases. The pathogenesis of bone sarcomas is strongly associated with dysregulation of local bone remodeling and increased osteolysis that plays a part in tumor development. In this context, bisphosphonates (BPs) have been proposed as a single agent or in combination with conventional drugs to block bone resorption and the vicious cycle established between bone and sarcoma cells. Pre-clinical in vitro studies revealed the potential "anti-tumor" activities of nitrogen-bisphosphonates (N-BPs). In pre-clinical models, N-BPs reduced significantly primary tumor growth in osteosarcoma and Ewing sarcoma, and the installation of lung metastases. In chondrosarcoma, N-BPs reduced the recurrence of local tumors after intralesional curettage, and increased overall survival. In pediatric and adult osteosarcoma patients, N-BPs have been assessed in combination with conventional chemotherapy and surgery in randomized phase 3 studies with no improvement in clinical outcome. The lack of benefit may potentially be explained by the biological impact of N-BPs on macrophage differentiation/recruitment which may alter CD8-T lymphocyte infiltration. Thanks to their considerable affinity for the mineralized extracellular matrix, BPs are an excellent platform for drug delivery in malignant bone sites with reduced systemic toxicity, which opens up new opportunities for their future use.
Thureau, Sébastien; Faivre, Jean Christophe; Assaker, Richard; Biver, Emmanuel; Confavreux, Cyrille B; Debiais, Françoise; Duterque-Coquillaud, Martine; Giammarile, Francesco; Heymann, Dominique; Lecouvet, Frédéric E; Morardet, Laetitia; Paycha, Frederic; Body, Jean-Jacques; Vieillard, Marie-Hélène
Adapting palliative radiation therapy for bone metastases during the Covid-19 pandemic: GEMO position paper Article de journal
Dans: J Bone Oncol, vol. 22, p. 100291, 2020, ISSN: 2212-1366.
@article{pmid32292693,
title = {Adapting palliative radiation therapy for bone metastases during the Covid-19 pandemic: GEMO position paper},
author = {Sébastien Thureau and Jean Christophe Faivre and Richard Assaker and Emmanuel Biver and Cyrille B Confavreux and Françoise Debiais and Martine Duterque-Coquillaud and Francesco Giammarile and Dominique Heymann and Frédéric E Lecouvet and Laetitia Morardet and Frederic Paycha and Jean-Jacques Body and Marie-Hélène Vieillard},
doi = {10.1016/j.jbo.2020.100291},
issn = {2212-1366},
year = {2020},
date = {2020-06-01},
urldate = {2020-06-01},
journal = {J Bone Oncol},
volume = {22},
pages = {100291},
abstract = {The current health crisis caused by COVID-19 is a challenge for oncology treatment, especially when it comes to radiotherapy. Cancer patients are already known to be very fragile and COVID-19 brings about the risk of severe respiratory complications. In order to treat patients safely while protecting medical teams, the entire health care system must optimize the way it approaches prevention and treatment at a time when social distancing is key to stemming this pandemic. All indications and treatment modalities must be re-discussed. This is particularly the case for radiotherapy of bone metastases for which it is possible to reduce the number of sessions, the frequency of transport and the complexity of treatments. These changes will have to be discussed according to the organization of each radiotherapy department and the health situation, while medical teams must remain vigilant about the risks of complications of bone metastases, particularly spinal metastases. In this short piece, the members of the GEMO (the European Study Group of Bone Metastases) offer a number of recommendations to achieve the above objectives, both in general and in relation to five of the most common situations on radiation therapy for bone metastases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The current health crisis caused by COVID-19 is a challenge for oncology treatment, especially when it comes to radiotherapy. Cancer patients are already known to be very fragile and COVID-19 brings about the risk of severe respiratory complications. In order to treat patients safely while protecting medical teams, the entire health care system must optimize the way it approaches prevention and treatment at a time when social distancing is key to stemming this pandemic. All indications and treatment modalities must be re-discussed. This is particularly the case for radiotherapy of bone metastases for which it is possible to reduce the number of sessions, the frequency of transport and the complexity of treatments. These changes will have to be discussed according to the organization of each radiotherapy department and the health situation, while medical teams must remain vigilant about the risks of complications of bone metastases, particularly spinal metastases. In this short piece, the members of the GEMO (the European Study Group of Bone Metastases) offer a number of recommendations to achieve the above objectives, both in general and in relation to five of the most common situations on radiation therapy for bone metastases.
Briand, Joséphine; Garnier, Delphine; Nadaradjane, Arulraj; Clément-Colmou, Karen; Potiron, Vincent; Supiot, Stéphane; Bougras-Cartron, Gwenola; Frenel, Jean-Sébastien; Heymann, Dominique; Vallette, François M; Cartron, Pierre-François
Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity Article de journal
Dans: Epigenomics, vol. 12, no. 5, p. 397–408, 2020, ISSN: 1750-192X.
@article{pmid32267172,
title = {Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity},
author = {Joséphine Briand and Delphine Garnier and Arulraj Nadaradjane and Karen Clément-Colmou and Vincent Potiron and Stéphane Supiot and Gwenola Bougras-Cartron and Jean-Sébastien Frenel and Dominique Heymann and François M Vallette and Pierre-François Cartron},
doi = {10.2217/epi-2019-0193},
issn = {1750-192X},
year = {2020},
date = {2020-04-08},
urldate = {2020-01-01},
journal = {Epigenomics},
volume = {12},
number = {5},
pages = {397--408},
abstract = { We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells. Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy. The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples. Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells. Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy. The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples. Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.
Heymann, Dominique; Verhille, Estelle; Veron, Vanessa; Vitre, Marie; Delmas, Florian; Henry, Cécile; Gouy, Yann; Amiand, Marie; Bard, Jean-Marie
Dans: Open Journal of Bioresources, vol. 7, p. 5, 2020.
@article{heymann2020centre,
title = {Centre de ressources Biologiques-Tumorothèque: bioresources and associated clinical data dedicated to translational research in oncology at the institut de cancérologie de l’Ouest, France},
author = {Dominique Heymann and Estelle Verhille and Vanessa Veron and Marie Vitre and Florian Delmas and Cécile Henry and Yann Gouy and Marie Amiand and Jean-Marie Bard},
doi = {10.5334/ojb.62},
year = {2020},
date = {2020-04-07},
urldate = {2020-01-01},
journal = {Open Journal of Bioresources},
volume = {7},
pages = {5},
abstract = {The Centre de Ressources Biologiques-Tumorothèque ICO is a biobank integrated in a clinical cancer center (ICO, Institut de Cancérologie de l’Ouest, Saint-Herblain, FR) that collects tissues (snap frozen, FFPE, TMA) and biological (serum, plasma, DNA, RNA, stools, etc) samples from oncology patients and dedicated to translational research. The biobank started its activities in 2002 and is certified NF S 96 900. Activities are framed by a quality management system with established and validated SOPs for all work procedures. Samples stored into the biobank are available for both academic as well as commercial researchers, through a defined access procedure. Currently the bioresources consist in more than 99.500 samples with informed consent and associated clinical data.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The Centre de Ressources Biologiques-Tumorothèque ICO is a biobank integrated in a clinical cancer center (ICO, Institut de Cancérologie de l’Ouest, Saint-Herblain, FR) that collects tissues (snap frozen, FFPE, TMA) and biological (serum, plasma, DNA, RNA, stools, etc) samples from oncology patients and dedicated to translational research. The biobank started its activities in 2002 and is certified NF S 96 900. Activities are framed by a quality management system with established and validated SOPs for all work procedures. Samples stored into the biobank are available for both academic as well as commercial researchers, through a defined access procedure. Currently the bioresources consist in more than 99.500 samples with informed consent and associated clinical data.
Gama, Andrea; Maman, Laura; Vargas-Franco, Jorge William; Omar, Rana; Royer, Bénédicte Brounais-Le; Yagita, Hideo; Babajko, Sylvie; Berdal, Ariane; Acevedo, Ana Carolina; Heymann, Dominique; Lézot, Frédéric; Castaneda, Beatriz
Primary Retention of Molars and RANKL Signaling Alteration during Craniofacial Growth Article de journal
Dans: J Clin Med, vol. 9, no. 4, 2020, ISSN: 2077-0383.
@article{pmid32218136,
title = {Primary Retention of Molars and RANKL Signaling Alteration during Craniofacial Growth},
author = {Andrea Gama and Laura Maman and Jorge William Vargas-Franco and Rana Omar and Bénédicte Brounais-Le Royer and Hideo Yagita and Sylvie Babajko and Ariane Berdal and Ana Carolina Acevedo and Dominique Heymann and Frédéric Lézot and Beatriz Castaneda},
doi = {10.3390/jcm9040898},
issn = {2077-0383},
year = {2020},
date = {2020-03-25},
urldate = {2020-03-01},
journal = {J Clin Med},
volume = {9},
number = {4},
abstract = {The primary retention of molars observed in clinic corresponds to a still-unexplained absence of molar eruption despite the presence of an eruption pathway, resembling the experimental transient inhibition of RANKL signaling in mice. The aim of the present study was to confront the hypothesis according to which the primary retention of molars is associated with transitory perturbations to RANKL signaling during growth as part of a wider craniofacial skeleton pattern. The experimental strategy was based on combining a clinical study and an animal study corresponding to the characterization of the craniofacial phenotypes of patients with primary retention of molars and analyses in mice of the consequences of transient inhibition of RANKL signaling on molar eruption and craniofacial growth. The clinical study validated the existence of a particular craniofacial phenotype in patients with primary retention of molars: a retromandibular skeletal class II typology with reduced mandibular dimensions which manifests itself at the dental level by a class II/2 with palatoversion of the upper incisors and anterior overbite. The animal study demonstrated that transient invalidation of RANKL signaling had an impact on the molar eruption process, the severity of which was dependent on the period of inhibition and was associated with a reduction in two craniofacial morphometric parameters: total skull length and craniofacial vault length. In conclusion, primary retention of molars may be proposed as part of the craniofacial skeleton phenotype associated with a transitory alteration in RANKL signaling during growth.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The primary retention of molars observed in clinic corresponds to a still-unexplained absence of molar eruption despite the presence of an eruption pathway, resembling the experimental transient inhibition of RANKL signaling in mice. The aim of the present study was to confront the hypothesis according to which the primary retention of molars is associated with transitory perturbations to RANKL signaling during growth as part of a wider craniofacial skeleton pattern. The experimental strategy was based on combining a clinical study and an animal study corresponding to the characterization of the craniofacial phenotypes of patients with primary retention of molars and analyses in mice of the consequences of transient inhibition of RANKL signaling on molar eruption and craniofacial growth. The clinical study validated the existence of a particular craniofacial phenotype in patients with primary retention of molars: a retromandibular skeletal class II typology with reduced mandibular dimensions which manifests itself at the dental level by a class II/2 with palatoversion of the upper incisors and anterior overbite. The animal study demonstrated that transient invalidation of RANKL signaling had an impact on the molar eruption process, the severity of which was dependent on the period of inhibition and was associated with a reduction in two craniofacial morphometric parameters: total skull length and craniofacial vault length. In conclusion, primary retention of molars may be proposed as part of the craniofacial skeleton phenotype associated with a transitory alteration in RANKL signaling during growth.
Gama, Andrea; Vargas-Franco, Jorge William; Mesa, Diana Carolina Sánchez; Bedoya, Elizabeth Restrepo; Amiaud, Jérome; Babajko, Sylvie; Berdal, Ariane; Acevedo, Ana Carolina; Heymann, Dominique; Lézot, Frédéric; Castaneda, Beatriz
Origins of Alterations to Null Mutant Mouse Dental Root Development Article de journal
Dans: Int J Mol Sci, vol. 21, no. 6, 2020, ISSN: 1422-0067.
@article{pmid32209985,
title = {Origins of Alterations to Null Mutant Mouse Dental Root Development},
author = {Andrea Gama and Jorge William Vargas-Franco and Diana Carolina Sánchez Mesa and Elizabeth Restrepo Bedoya and Jérome Amiaud and Sylvie Babajko and Ariane Berdal and Ana Carolina Acevedo and Dominique Heymann and Frédéric Lézot and Beatriz Castaneda},
doi = {10.3390/ijms21062201},
issn = {1422-0067},
year = {2020},
date = {2020-03-23},
urldate = {2020-03-01},
journal = {Int J Mol Sci},
volume = {21},
number = {6},
abstract = {The purpose of the present study was to assess the early stages of development of mouse first molar roots in the osteopetrotic context of RANKL invalidation in order to demonstrate that the radicular phenotype observed resulted not only from defective osteoclasts, but also from loss of cell-to-cell communication among dental, periodontium and alveolar bone cells involving RANKL signaling. Two experimental models were used in this study: mutants with permanent RANKL invalidation, and C57BL/6J mice injected during the first postnatal week with a RANKL neutralizing antibody corresponding to a transient RANKL invalidation. The dento-alveolar complex was systematically analyzed using micro-CT, and histological and immunohistochemical approaches. These experiments showed that the root elongation alterations observed in the mice were associated with reduced proliferation of the RANK-expressing HERS cells with a significant decrease in proliferating cell nuclear antigen (PCNA) expression and a significant increase in P21 expression. The phenotypic comparison of the adult first molar root at 35 days between permanent and transitory invalidations of RANKL made it possible to demonstrate that alterations in dental root development have at least two origins, one intrinsic and linked to proliferation/differentiation perturbations in dental-root-forming cells, the other extrinsic and corresponding to disturbances of bone cell differentiation/function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The purpose of the present study was to assess the early stages of development of mouse first molar roots in the osteopetrotic context of RANKL invalidation in order to demonstrate that the radicular phenotype observed resulted not only from defective osteoclasts, but also from loss of cell-to-cell communication among dental, periodontium and alveolar bone cells involving RANKL signaling. Two experimental models were used in this study: mutants with permanent RANKL invalidation, and C57BL/6J mice injected during the first postnatal week with a RANKL neutralizing antibody corresponding to a transient RANKL invalidation. The dento-alveolar complex was systematically analyzed using micro-CT, and histological and immunohistochemical approaches. These experiments showed that the root elongation alterations observed in the mice were associated with reduced proliferation of the RANK-expressing HERS cells with a significant decrease in proliferating cell nuclear antigen (PCNA) expression and a significant increase in P21 expression. The phenotypic comparison of the adult first molar root at 35 days between permanent and transitory invalidations of RANKL made it possible to demonstrate that alterations in dental root development have at least two origins, one intrinsic and linked to proliferation/differentiation perturbations in dental-root-forming cells, the other extrinsic and corresponding to disturbances of bone cell differentiation/function.
Moukengue, Brice; Brown, Hannah K; Charrier, Céline; Battaglia, Séverine; Baud'huin, Marc; Quillard, Thibaut; Pham, Therese M; Pateras, Ioannis S; Gorgoulis, Vassilis G; Helleday, Thomas; Heymann, Dominique; Berglund, Ulrika Warpman; Ory, Benjamin; Lamoureux, Francois
TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model Article de journal
Dans: EBioMedicine, vol. 53, p. 102704, 2020, ISSN: 2352-3964.
@article{pmid32151797,
title = {TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model},
author = {Brice Moukengue and Hannah K Brown and Céline Charrier and Séverine Battaglia and Marc Baud'huin and Thibaut Quillard and Therese M Pham and Ioannis S Pateras and Vassilis G Gorgoulis and Thomas Helleday and Dominique Heymann and Ulrika Warpman Berglund and Benjamin Ory and Francois Lamoureux},
doi = {10.1016/j.ebiom.2020.102704},
issn = {2352-3964},
year = {2020},
date = {2020-03-07},
urldate = {2020-03-07},
journal = {EBioMedicine},
volume = {53},
pages = {102704},
abstract = {BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers.
METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases.
FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases.
INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma.
FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers.
METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases.
FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases.
INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma.
FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases.
FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases.
INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma.
FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
Cheray, Mathilde; Etcheverry, Amandine; Jacques, Camille; Pacaud, Romain; Bougras-Cartron, Gwenola; Aubry, Marc; Denoual, Florent; Peterlongo, Pierre; Nadaradjane, Arulraj; Briand, Joséphine; Akcha, Farida; Heymann, Dominique; Vallette, François M; Mosser, Jean; Ory, Benjamin; Cartron, Pierre-François
Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme Article de journal
Dans: Mol Cancer, vol. 19, no. 1, p. 36, 2020, ISSN: 1476-4598.
@article{pmid32098627,
title = {Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme},
author = {Mathilde Cheray and Amandine Etcheverry and Camille Jacques and Romain Pacaud and Gwenola Bougras-Cartron and Marc Aubry and Florent Denoual and Pierre Peterlongo and Arulraj Nadaradjane and Joséphine Briand and Farida Akcha and Dominique Heymann and François M Vallette and Jean Mosser and Benjamin Ory and Pierre-François Cartron},
doi = {10.1186/s12943-020-01155-z},
issn = {1476-4598},
year = {2020},
date = {2020-02-25},
urldate = {2020-01-01},
journal = {Mol Cancer},
volume = {19},
number = {1},
pages = {36},
abstract = {BACKGROUND: Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM).
METHODS: RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.
RESULTS: Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.
CONCLUSION: Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM).
METHODS: RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.
RESULTS: Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.
CONCLUSION: Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.
METHODS: RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.
RESULTS: Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.
CONCLUSION: Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.
Duforestel, Manon; Briand, Joséphine; Bougras-Cartron, Gwenola; Heymann, Dominique; Frenel, Jean-Sébastien; Vallette, François M; Cartron, Pierre-François
Cell-free circulating epimarks in cancer monitoring Article de journal
Dans: Epigenomics, vol. 12, no. 2, p. 145–155, 2020, ISSN: 1750-192X.
@article{pmid31916450,
title = {Cell-free circulating epimarks in cancer monitoring},
author = {Manon Duforestel and Joséphine Briand and Gwenola Bougras-Cartron and Dominique Heymann and Jean-Sébastien Frenel and François M Vallette and Pierre-François Cartron},
doi = {10.2217/epi-2019-0170},
issn = {1750-192X},
year = {2020},
date = {2020-01-09},
urldate = {2020-01-01},
journal = {Epigenomics},
volume = {12},
number = {2},
pages = {145--155},
abstract = {Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.
Grünewald, Thomas Gp; Alonso, Marta; Avnet, Sofia; Banito, Ana; Burdach, Stefan; Cidre-Aranaz, Florencia; Pompo, Gemma Di; Distel, Martin; Dorado-Garcia, Heathcliff; Garcia-Castro, Javier; González-González, Laura; Grigoriadis, Agamemnon E; Kasan, Merve; Koelsche, Christian; Krumbholz, Manuela; Lecanda, Fernando; Lemma, Silvia; Longo, Dario L; Madrigal-Esquivel, Claudia; Morales-Molina, Álvaro; Musa, Julian; Ohmura, Shunya; Ory, Benjamin; Pereira-Silva, Miguel; Perut, Francesca; Rodriguez, Rene; Seeling, Carolin; Shaaili, Nada Al; Shaabani, Shabnam; Shiavone, Kristina; Sinha, Snehadri; Tomazou, Eleni M; Trautmann, Marcel; Vela, Maria; Versleijen-Jonkers, Yvonne Mh; Visgauss, Julia; Zalacain, Marta; Schober, Sebastian J; Lissat, Andrej; English, William R; Baldini, Nicola; Heymann, Dominique
Sarcoma treatment in the era of molecular medicine Article de journal
Dans: EMBO Mol Med, vol. 12, no. 11, p. e11131, 2020, ISSN: 1757-4684.
@article{pmid33047515,
title = {Sarcoma treatment in the era of molecular medicine},
author = {Thomas Gp Grünewald and Marta Alonso and Sofia Avnet and Ana Banito and Stefan Burdach and Florencia Cidre-Aranaz and Gemma Di Pompo and Martin Distel and Heathcliff Dorado-Garcia and Javier Garcia-Castro and Laura González-González and Agamemnon E Grigoriadis and Merve Kasan and Christian Koelsche and Manuela Krumbholz and Fernando Lecanda and Silvia Lemma and Dario L Longo and Claudia Madrigal-Esquivel and Álvaro Morales-Molina and Julian Musa and Shunya Ohmura and Benjamin Ory and Miguel Pereira-Silva and Francesca Perut and Rene Rodriguez and Carolin Seeling and Nada Al Shaaili and Shabnam Shaabani and Kristina Shiavone and Snehadri Sinha and Eleni M Tomazou and Marcel Trautmann and Maria Vela and Yvonne Mh Versleijen-Jonkers and Julia Visgauss and Marta Zalacain and Sebastian J Schober and Andrej Lissat and William R English and Nicola Baldini and Dominique Heymann},
doi = {10.15252/emmm.201911131},
issn = {1757-4684},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {EMBO Mol Med},
volume = {12},
number = {11},
pages = {e11131},
abstract = {Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
Mignard, Vincent; Dubois, Nolwenn; Lanoé, Didier; Joalland, Marie-Pierre; Oliver, Lisa; Pecqueur, Claire; Heymann, Dominique; Paris, François; Vallette, François M; Lalier, Lisenn
Sphingolipid distribution at mitochondria-associated membranes (MAMs) upon induction of apoptosis Article de journal
Dans: J Lipid Res, vol. 61, no. 7, p. 1025–1037, 2020, ISSN: 1539-7262.
@article{pmid32350079,
title = {Sphingolipid distribution at mitochondria-associated membranes (MAMs) upon induction of apoptosis},
author = {Vincent Mignard and Nolwenn Dubois and Didier Lanoé and Marie-Pierre Joalland and Lisa Oliver and Claire Pecqueur and Dominique Heymann and François Paris and François M Vallette and Lisenn Lalier},
doi = {10.1194/jlr.RA120000628},
issn = {1539-7262},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {J Lipid Res},
volume = {61},
number = {7},
pages = {1025--1037},
abstract = {The levels and composition of sphingolipids and related metabolites are altered in aging and in common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC-MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified ER, mitochondria-associated membranes (MAMs), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, SM in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine-induced apoptosis in U251 cells. Ceramide (especially C16-ceramide) levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and SM, but sphingosine and lactosyl- and glycosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when SM levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and the ER during the early steps of apoptosis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The levels and composition of sphingolipids and related metabolites are altered in aging and in common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC-MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified ER, mitochondria-associated membranes (MAMs), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, SM in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine-induced apoptosis in U251 cells. Ceramide (especially C16-ceramide) levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and SM, but sphingosine and lactosyl- and glycosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when SM levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and the ER during the early steps of apoptosis.
2019
Taves, Sarah; Sun, Junjiang; Livingston, Eric W; Chen, Xin; Amiaud, Jerome; Brion, Regis; Hannah, William B; Bateman, Ted A; Heymann, Dominique; Monahan, Paul E
Hemophilia A and B mice, but not VWFmice, display bone defects in congenital development and remodeling after injury Article de journal
Dans: Sci Rep, vol. 9, no. 1, p. 14428, 2019, ISSN: 2045-2322.
@article{pmid31594977,
title = {Hemophilia A and B mice, but not VWFmice, display bone defects in congenital development and remodeling after injury},
author = {Sarah Taves and Junjiang Sun and Eric W Livingston and Xin Chen and Jerome Amiaud and Regis Brion and William B Hannah and Ted A Bateman and Dominique Heymann and Paul E Monahan},
doi = {10.1038/s41598-019-50787-9},
issn = {2045-2322},
year = {2019},
date = {2019-10-08},
urldate = {2019-10-08},
journal = {Sci Rep},
volume = {9},
number = {1},
pages = {14428},
abstract = {While joint damage is the primary co-morbidity of hemophilia, osteoporosis and osteopenia are also observed. Coagulation factor VIII deficient (FVIII) mice develop an osteoporotic phenotype in the absence of induced hemarthrosis that is exacerbated two weeks after an induced joint injury. Here we have compared comprehensively the bone health of clotting factor VIII, factor IX, and Von Willebrand Factor knockout (FVIII, FIX, and VWF respectively) mice both in the absence of joint hemorrhage and following induced joint injury. We found FVIII and FIX mice, but not VWF mice, developmentally have an osteoporotic phenotype. Unilateral induced hemarthrosis causes further bone damage in both FVIII and FIX mice, but has little effect on VWF bone health, indicating that the FVIII.VWF complex is not required for normal bone remodeling in vivo. To further investigate the bone healing following hemarthrosis in hemophilia we examined a two week time course using microCT, serum chemistry, and histological analysis. Elevated ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL), increased osterix osteoblastic cells, and decreased smoothness of the cortical bone surface were evident within several days of injury, indicative of acute heterotopic mineralization along the cortical surface. This was closely followed by increased interleukin-6 (IL-6) levels, increased osteoclast numbers, and significant trabecular bone loss. Uncoupled and disorganized bone formation and resorption continued for the duration of the study resulting in significant deterioration of the joint. Further elucidation of the shared mechanisms underlying abnormal bone homeostasis in the absence of FVIII or FIX is needed to guide evidence-based approaches to the screening and treatment of the prevalent bone defects in hemophilia A and B.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
While joint damage is the primary co-morbidity of hemophilia, osteoporosis and osteopenia are also observed. Coagulation factor VIII deficient (FVIII) mice develop an osteoporotic phenotype in the absence of induced hemarthrosis that is exacerbated two weeks after an induced joint injury. Here we have compared comprehensively the bone health of clotting factor VIII, factor IX, and Von Willebrand Factor knockout (FVIII, FIX, and VWF respectively) mice both in the absence of joint hemorrhage and following induced joint injury. We found FVIII and FIX mice, but not VWF mice, developmentally have an osteoporotic phenotype. Unilateral induced hemarthrosis causes further bone damage in both FVIII and FIX mice, but has little effect on VWF bone health, indicating that the FVIII.VWF complex is not required for normal bone remodeling in vivo. To further investigate the bone healing following hemarthrosis in hemophilia we examined a two week time course using microCT, serum chemistry, and histological analysis. Elevated ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL), increased osterix osteoblastic cells, and decreased smoothness of the cortical bone surface were evident within several days of injury, indicative of acute heterotopic mineralization along the cortical surface. This was closely followed by increased interleukin-6 (IL-6) levels, increased osteoclast numbers, and significant trabecular bone loss. Uncoupled and disorganized bone formation and resorption continued for the duration of the study resulting in significant deterioration of the joint. Further elucidation of the shared mechanisms underlying abnormal bone homeostasis in the absence of FVIII or FIX is needed to guide evidence-based approaches to the screening and treatment of the prevalent bone defects in hemophilia A and B.
Alvarez, Carla; Monasterio, Gustavo; Cavalla, Franco; Córdova, Luis A; Hernández, Marcela; Heymann, Dominique; Garlet, Gustavo P; Sorsa, Timo; Pärnänen, Pirjo; Lee, Hsi-Ming; Golub, Lorne M; Vernal, Rolando; Kantarci, Alpdogan
Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms Article de journal
Dans: Front Immunol, vol. 10, p. 1664, 2019, ISSN: 1664-3224.
@article{pmid31379856,
title = {Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms},
author = {Carla Alvarez and Gustavo Monasterio and Franco Cavalla and Luis A Córdova and Marcela Hernández and Dominique Heymann and Gustavo P Garlet and Timo Sorsa and Pirjo Pärnänen and Hsi-Ming Lee and Lorne M Golub and Rolando Vernal and Alpdogan Kantarci},
doi = {10.3389/fimmu.2019.01664},
issn = {1664-3224},
year = {2019},
date = {2019-07-18},
urldate = {2019-07-18},
journal = {Front Immunol},
volume = {10},
pages = {1664},
abstract = {The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.
Tellez-Gabriel, Marta; Heymann, Marie-Françoise; Heymann, Dominique
Circulating Tumor Cells as a Tool for Assessing Tumor Heterogeneity Article de journal
Dans: Theranostics, vol. 9, no. 16, p. 4580–4594, 2019, ISSN: 1838-7640.
@article{pmid31367241,
title = {Circulating Tumor Cells as a Tool for Assessing Tumor Heterogeneity},
author = {Marta Tellez-Gabriel and Marie-Françoise Heymann and Dominique Heymann},
doi = {10.7150/thno.34337},
issn = {1838-7640},
year = {2019},
date = {2019-06-19},
urldate = {2019-06-19},
journal = {Theranostics},
volume = {9},
number = {16},
pages = {4580--4594},
abstract = {Tumor heterogeneity is the major cause of failure in cancer prognosis and prediction. Accurately detecting heterogeneity for the development of biomarkers and the detection of the clones resistant to therapy is one of the main goals of contemporary medicine. Metastases belong to the natural history of cancer. The present review gives an overview on the origin of tumor heterogeneity. Recent progress has made it possible to isolate and characterize circulating tumor cells (CTCs), which are the drivers of the disease between the primary sites and metastatic foci. The most recent methods for characterizing CTCs are summarized and we discuss the power of CTC profiling for analyzing tumor heterogeneity in early and advanced diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Tumor heterogeneity is the major cause of failure in cancer prognosis and prediction. Accurately detecting heterogeneity for the development of biomarkers and the detection of the clones resistant to therapy is one of the main goals of contemporary medicine. Metastases belong to the natural history of cancer. The present review gives an overview on the origin of tumor heterogeneity. Recent progress has made it possible to isolate and characterize circulating tumor cells (CTCs), which are the drivers of the disease between the primary sites and metastatic foci. The most recent methods for characterizing CTCs are summarized and we discuss the power of CTC profiling for analyzing tumor heterogeneity in early and advanced diseases.
2017
Brown, Hannah K; Tellez-Gabriel, Marta; Heymann, Dominique
Cancer stem cells in osteosarcoma Article de journal
Dans: Cancer Lett, vol. 386, p. 189–195, 2017, ISSN: 1872-7980.
@article{pmid27894960,
title = {Cancer stem cells in osteosarcoma},
author = {Hannah K Brown and Marta Tellez-Gabriel and Dominique Heymann},
doi = {10.1016/j.canlet.2016.11.019},
issn = {1872-7980},
year = {2017},
date = {2017-01-01},
urldate = {2017-01-01},
journal = {Cancer Lett},
volume = {386},
pages = {189--195},
abstract = {Osteosarcoma is the most common primary bone tumour in children and adolescents and advanced osteosarcoma patients with evidence of metastasis share a poor prognosis. Osteosarcoma frequently gains resistance to standard therapies highlighting the need for improved treatment regimens and identification of novel therapeutic targets. Cancer stem cells (CSC) represent a sub-type of tumour cells attributed to critical steps in cancer including tumour propagation, therapy resistance, recurrence and in some cases metastasis. Recent published work demonstrates evidence of cancer stem cell phenotypes in osteosarcoma with links to drug resistance and tumorigenesis. In this review we will discuss the commonly used isolation techniques for cancer stem cells in osteosarcoma as well as the identified biochemical and molecular markers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Osteosarcoma is the most common primary bone tumour in children and adolescents and advanced osteosarcoma patients with evidence of metastasis share a poor prognosis. Osteosarcoma frequently gains resistance to standard therapies highlighting the need for improved treatment regimens and identification of novel therapeutic targets. Cancer stem cells (CSC) represent a sub-type of tumour cells attributed to critical steps in cancer including tumour propagation, therapy resistance, recurrence and in some cases metastasis. Recent published work demonstrates evidence of cancer stem cell phenotypes in osteosarcoma with links to drug resistance and tumorigenesis. In this review we will discuss the commonly used isolation techniques for cancer stem cells in osteosarcoma as well as the identified biochemical and molecular markers.