@article{Young2024,

title = {CIRCUS: CIRCUlating tumour cells in soft tissue Sarcoma - a short report},

author = {Robin J. Young and Joanna E. Chowdry and Denis Cochonneau and Dominique Heymann},

doi = {10.20517/cdr.2024.149},

issn = {2578-532X},

year  = {2024},

date = {2024-12-13},

urldate = {2024-12-13},

journal = {Cancer Drug Resist},

publisher = {OAE Publishing Inc.},

abstract = {Aims:  Circulating tumour cells (CTCs) can be detected in peripheral blood using their physical properties (increased size and less deformable than normal circulating blood cells) or using cell surface markers. The study of these CTCs should provide important insights into tumour biology, including mechanisms of drug resistance. We performed a pilot study (IRAS ID: 235459) to evaluate if CTCs could be isolated from peripheral blood samples collected from soft tissue sarcoma (STS) patients.

Methods:  We used a combined approach that first enriched samples for CTCs using a microfluidic cassette via ParosrtixTMPR1, and then sorted cells stained for vimentin and cytokeratin using the DEPArrayTM. The total circulating cell-free DNA (cfDNA) level was also analysed. Data were correlated with clinical parameters.

Results:  13 patients were recruited to this study: 7 patients with localised disease and 6 patients with metastatic disease. CTCs exhibited a high heterogeneity based on their expression of mesenchymal and epithelial biomarkers. There was no significant difference in the number of CTCs between patients with localised versus metastatic disease. We observed no correlation between CTC numbers and cfDNA; however, the number of CTCs did correlate with primary tumour size.

Conclusion:  The present study demonstrates the presence of CTCs in STS patients with localised and advanced disease. Further and larger studies are needed to characterise STS CTCs and to evaluate their prognostic significance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Oliver2024,

title = {Transcriptional landscape of the interaction of human Mesenchymal Stem Cells with Glioblastoma in bioprinted co-cultures},

author = {Lisa Oliver and Yuna Landais and Catherine Gratas and Pierre-François Cartron and François Paris and Dominique Heymann and François M. Vallette and Aurelien Serandour},

doi = {10.1186/s13287-024-04022-6},

issn = {1757-6512},

year  = {2024},

date = {2024-12-00},

urldate = {2024-12-00},

journal = {Stem Cell Res Ther},

volume = {15},

number = {1},

publisher = {Springer Science and Business Media LLC},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cordova_why_2024,

title = {Why are osteoporosis patients treated with antiresorptive therapies considered like oncology patients regarding their oral health care?},

author = {Luis A. Cordova and David González-Quintanilla and Dominique Heymann},

url = {https://doi.org/10.1007/s00198-024-07173-7},

doi = {10.1007/s00198-024-07173-7},

issn = {1433-2965},

year  = {2024},

date = {2024-06-01},

urldate = {2024-06-01},

journal = {Osteoporosis International},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38547578b,

title = {A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma},

author = {Verónica Rey and Juan Tornín and Juan Jose Alba-Linares and Cristina Robledo and Dzohara Murillo and Aida Rodríguez and Borja Gallego and Carmen Huergo and Cristina Viera and Alejandro Braña and Aurora Astudillo and Dominique Heymann and Karoly Szuhai and Judith V M G Bovée and Agustín F Fernández and Mario F Fraga and Javier Alonso and René Rodríguez},

url = {inserm-04524777v1 },

doi = {10.1016/j.ebiom.2024.105090},

issn = {2352-3964},

year  = {2024},

date = {2024-04-01},

urldate = {2024-04-01},

journal = {EBioMedicine},

volume = {102},

pages = {105090},

abstract = {BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth.



METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses).



FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors.



INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas.



FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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

 inserm-04501791v1 },

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}

}

@article{cancers16132351,

title = {A Prospective Observational Cohort Study for Newly Diagnosed Osteosarcoma Patients in the UK: ICONIC Study Initial Results},

author = {Alexa Childs and Craig Gerrand and Bernadette Brennan and Robin Young and Kenneth S. Rankin and Michael Parry and Jonathan Stevenson and Adrienne M. Flanagan and Rachel M. Taylor and Lorna Fern and Dominique Heymann and Filipa Vance and Jenny Sherriff and Saurabh Singh and Rubina Begum and Sharon L. Forsyth and Krystyna Reczko and Kate Sparksman and William Wilson and Sandra J. Strauss},

url = {https://www.mdpi.com/2072-6694/16/13/2351},

doi = {10.3390/cancers16132351},

issn = {2072-6694},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {Cancers},

volume = {16},

number = {13},

abstract = {There has been little change to the standard treatment for osteosarcoma (OS) over the last 25 years and there is an unmet need to identify new biomarkers and novel therapeutic approaches if outcomes are to improve. Furthermore, there is limited evidence on the impact of OS treatment on patient-reported outcomes (PROs). ICONIC (Improving Outcomes through Collaboration in Osteosarcoma; NCT04132895) is a prospective observational cohort study recruiting newly diagnosed OS patients across the United Kingdom (UK) with matched longitudinal collection of clinical, biological, and PRO data. During Stage 1, which assessed the feasibility of recruitment and data collection, 102 patients were recruited at 22 sites with representation from patient groups frequently excluded in OS studies, including patients over 50 years and those with less common primary sites. The feasibility of collecting clinical and biological samples, in addition to PRO data, has been established and there is ongoing analysis of these data as part of Stage 2. ICONIC will provide a unique, prospective cohort of newly diagnosed OS patients representative of the UK patient population, with fully annotated clinical outcomes linked to molecularly characterised biospecimens, allowing for comprehensive analyses to better understand biology and develop new biomarkers and novel therapeutic approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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

 inserm-04501796v1 },

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}

}

@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},

url = {hal-04210189v1 },

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}

}

@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

inserm-04501799v1 },

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}

}

@article{pmid37148979,

title = {Pharmacological options in the treatment of osteogenesis imperfecta: A comprehensive review of clinical and potential alternatives},

author = {Javier Muñoz-Garcia and Dominique Heymann and Irina Giurgea and Marie Legendre and Serge Amselem and Beatriz Castañeda and Frédéric Lézot and Jorge William Vargas-Franco},

url = { inserm-04100355v1 },

doi = {10.1016/j.bcp.2023.115584},

issn = {1873-2968},

year  = {2023},

date = {2023-07-01},

urldate = {2023-07-01},

journal = {Biochem Pharmacol},

volume = {213},

pages = {115584},

abstract = {Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The severity of these manifestations makes it possible to classify OI into different subtypes based on the main clinical features. This review aims to outline and describe the current pharmacological alternatives for treating OI, grounded on clinical and preclinical reports, such as antiresorptive agents, anabolic agents, growth hormone, and anti-TGFβ antibody, among other less used agents. The different options and their pharmacokinetic and pharmacodynamic properties will be reviewed and discussed, focusing on the variability of their response and the molecular mechanisms involved to attain the main clinical goals, which include decreasing fracture incidence, improving pain, and promoting growth, mobility, and functional independence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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

inserm-04119793v1 },

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}

}

@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

hal-04254114v1 },

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}

}

@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}

}

@article{pmid37869710,

title = {Technical report: liquid overlay technique allows the generation of homogeneous osteosarcoma, glioblastoma, lung and prostate adenocarcinoma spheroids that can be used for drug cytotoxicity measurements},

author = {Camille Jubelin and Javier Muñoz-Garcia and Denis Cochonneau and Emilie Ollivier and François Vallette and Marie-Françoise Heymann and Lisa Oliver and Dominique Heymann},

url = { inserm-04501811v1 },

doi = {10.3389/fbioe.2023.1260049},

issn = {2296-4185},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Front Bioeng Biotechnol},

volume = {11},

pages = {1260049},

abstract = { The mechanisms involved in cancer initiation, progression, drug resistance, and disease recurrence are traditionally investigated through  adherent monolayer (2D) cell models. However, solid malignant tumor growth is characterized by progression in three dimensions (3D), and an increasing amount of evidence suggests that 3D culture models, such as spheroids, are suitable for mimicking cancer development. The aim of this report was to reaffirm the relevance of simpler 3D culture methods to produce highly reproducible spheroids, especially in the context of drug cytotoxicity measurements.  Human A549 lung adenocarcinoma, LnCaP prostate adenocarcinoma, MNNG/HOS osteosarcoma and U251 glioblastoma cell lines were grown into spheroids for 20 days using either Liquid Overlay Technique (LOT) or Hanging Drop (HD) in various culture plates. Their morphology was examined by microscopy. Sensitivity to doxorubicin was compared between MNNG/HOS cells grown in 2D and 3D.  For all cell lines studied, the morphology of spheroids generated in round-bottom multiwell plates was more repeatable than that of those generated in flat-bottom multiwell plates. HD had no significant advantage over LOT when the spheroids were cultured in round-bottom plates. Finally, the IC of doxorubicin on MNNG/HOS cultured in 3D was 18.8 times higher than in 2D cultures (3D IC = 15.07 ± 0.3 µM; 2D IC = 0.8 ± 0.4 µM; * < 0.05).  In conclusion, we propose that the LOT method, despite and because of its simplicity, is a relevant 3D model for drug response measurements that could be scaled up for high throughput screening.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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

 inserm-04056943v1 },

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}

}

@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

 inserm-04001934v1 },

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}

}

@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},

url = {inserm-04502548v1 },

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}

}

@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},

url = {inserm-03746641v1 },

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}

}

@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},

url = {inserm-03659450v1 },

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}

}

@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},

url = { hal-03798394v1 },

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}

}

@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},

url = {inserm-03878079v1 },

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}

}

@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/

 hal-03550024v1 },

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}

}

@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

inserm-03625367v1 },

doi = {10.3390/cancers14071765},

issn = {2072-6694},

year  = {2022},

date = {2022-03-30},

urldate = {2022-03-30},

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}

}

@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},

url = { inserm-03550410v1 },

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}

}

@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},

url = {hal-03600694v1 },

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}

}

@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}

}

@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}

}

@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}

}