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1. Involvement of the TGF-β Signaling Pathway in the Development of YAP-Driven Osteosarcoma Lung Metastasis

Author

Morice, Sarah, Danieau, Geoffroy, Tesfaye, Robel, Mullard, Mathilde, Brion, Régis, Dupuy, Maryne, Ory, Benjamin, Brounais-Le Royer, Bénédicte, Corre, Isabelle, Redini, Françoise, Verrecchia, Franck, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), and CORRE, Isabelle

Subjects
[SDV] Life Sciences [q-bio], Oncology, Hippo, TGF-b/Smad3, TEAD, osteosarcoma, [SDV]Life Sciences [q-bio], lung metastases, YAP, Original Research, TGF-β/Smad3
Abstract

Background The poor survival rate of patients with osteosarcoma (OS), specifically with metastases at diagnosis, undergoes the urgency to develop new therapeutic strategies. Although we recently demonstrated the key role of YAP/TEAD signaling in the growth of OS primary tumor, the molecular mechanisms by which YAP regulates metastases development remain poorly understood. Methods The molecular mechanisms by which YAP regulates metastases development were studied using an overexpression of mutated forms of YAP able or not able to interact with TEAD. Molecular signatures were identified using RNA-sequencing analysis and gene set enrichment. Interactions between YAP and Smad3 were studied using proximity ligation assay (PLA), immunoprecipitation, and promoter/specific gene assays. The involvement of the TGF-β pathway in the ability of YAP to stimulate metastatic development in vivo was studied using an inhibitor of the TGF-β cascade in a preclinical model of OS and in vitro on the ability of OS cells to migrate and invade. Results Our work shows that a high YAP expression is associated with the presence of lung metastases which predicts a poor prognosis. Molecular analysis indicates that TGF-β signaling is involved in YAP-driven osteosarcoma cell pro-migratory phenotype, epithelial mesenchymal transition, cell migration, and in vivo lung metastasis development. Regardless of its ability to bind to TEAD, YAP interacts with Smad3 and stimulates the transcriptional activity of TGF-β/Smad3, thereby enhancing the ability of TGF-β to stimulate lung metastasis development. Conclusions We demonstrated the crucial involvement of the TGF-β/Smad3 signaling pathway in YAP-driven lung metastasis development in OS.

Published
2021

2. Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme

Author

Cheray, Mathilde, Etcheverry, Amandine, Jacques, Camille, Pacaud, Romain, Bougras-Cartron, Gwenola, Aubry, Marc, Denoual, Florent, Peterlongo, Pierre, Nadaradjane, Arulraj, Briand, Josephine, Akcha, Farida, Heymann, Dominique, Vallette, François M, Mosser, Jean, Ory, Benjamin, Cartron, Pierre-Francois, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Nantes (UN), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), LabEX IGO Immunothérapie Grand Ouest, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Université de Rennes (UNIV-RENNES), Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut Français de Recherche pour l'Exploitation de la Mer - Atlantique (IFREMER Atlantique), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Nantes Université (Nantes Univ), Université de Rennes (UR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Chard-Hutchinson, Xavier

Subjects
AGO4, [SDV]Life Sciences [q-bio], Mice, Nude, Apoptosis, lcsh:RC254-282, DNA Methyltransferase 3A, Cytosine, Mice, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, DNA (Cytosine-5-)-Methyltransferases, Eukaryotic Initiation Factors, Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, miRNA, Epitranscriptomics, Research, DNA Methylation, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Xenograft Model Antitumor Assays, Cytosine-methylation, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Survival Rate, MicroRNAs, Argonaute Proteins, DNMT3A, Epigenetics, Glioblastoma
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. Graphical abstract

Published
2020

3. Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas

Author

Jacques, Camille, Tesfaye, Robel, Lavaud, Melanie, Georges, Steven, Baud'Huin, Marc, Lamoureux, François, Ory, Benjamin, Baud’huin, Marc, Equipe Labellisée LIGUE 2012 [Nantes], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
musculoskeletal diseases, Osteoblasts, [SDV]Life Sciences [q-bio], Bone Neoplasms, Cell Differentiation, Review, bone, microRNAs, Cell Transformation, Neoplastic, lcsh:Biology (General), osteosarcoma, Animals, Humans, Tumor Suppressor Protein p53, lcsh:QH301-705.5
Abstract

International audience; The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.

Published
2020

4. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases 1 development in osteosarcoma model 2 3

Author

Moukengue, Brice, Brown, Hannah, Charrier, Eline, Battaglia, Everine, Baud'Huin, Marc, Quillard, Thibaut, Pham, Therese, Pateras, Ioannis, Gorgoulis, Vassilis, Helleday, Thomas, Heymann, Dominique, Warpman Berglund, Ulrika, Ory, Benjamin, Lamoureux, François, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Oncology and Metabolism [Sheffield, UK] (European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Department of Oncology and Metabolism [Sheffield, UK], Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm], National and Kapodistrian University of Athens (NKUA), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), and maurice, sandrine

Subjects
Osteosarcoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, DNA damage, ROS, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone tumours, MTH1
Abstract

International audience; 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 res-ponders 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 Sant e.

Published
2020

5. Identification of genomic differences among peripheral arterial beds in atherosclerotic and healthy arteries

Author

Steenman, Marja, Espitia, Olivier, Maurel, Blandine, Guyomarch, Beatrice, Heymann, Marie-Françoise, Pistorius, Marc-Antoine, Ory, Benjamin, Heymann, Dominique, Houlgatte, Rémi, Gouëffic, Yann, Quillard, Thibaut, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de chirurgie vasculaire [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Délégation à la Recherche Clinique et à l'Innovation [CHRU Nancy] (DRCI), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), This work was funded by an Allocation Nationale de Recherche (ANR) for physiopathology and by an inter-regional Programme Hospitalier de Recherche Clinique (PHRC). T. Quillard received financial support from the European commission (Marie Sklodowska-Curie Actions, Individual Fellowships), the Fondation de l’Avenir (Paris, France), the University Hospital of Nantes (CHU Nantes, Nantes, France), and the Fédération Francaise de Cardiologie (Paris, France)., maurice, sandrine, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Male, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Genome, Human, Gene Expression Profiling, lcsh:R, Calcinosis, lcsh:Medicine, Arteries, Middle Aged, Atherosclerosis, Article, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Case-Control Studies, Humans, Female, lcsh:Q, lcsh:Science, Aged
Abstract

International audience; Calcification is independently associated with cardiovascular events and morbidity. The calcification burden in atherosclerotic lesions quantitatively and qualitatively differs between arterial beds. Cardiovascular risk factors (CVRF) differentially affect plaque development between arterial beds. The aim of this study was to evaluate the impact of CVRF on atherosclerotic plaque calcification and to further study the molecular arterial heterogeneity that could account for these differences. Histological analysis was performed on atherosclerotic plaques from 153 carotid, 97 femoral and 28 infrapopliteal arteries. CVRF showed minor associations with plaque calcification: age and hypertension affected only the overall presence of calcification but not the type of the calcification, which significantly differed between arterial beds. Transcriptome analysis revealed distinct gene expression profiles associated with each territory in atherosclerotic and healthy arteries. Canonical pathway analysis showed the preferential involvement of immune system-related processes in both atherosclerotic and healthy carotid arteries. Bone development-related genes were among those mostly enriched in atherosclerotic and healthy femoral arteries, which are more prone to developing endochondral calcification. This study highlights the heterogeneous nature of arteries from different peripheral vascular beds and contributes to a better understanding of atherosclerosis formation and evolution. Vascular calcification is an independent predicting factor for cardiovascular events and morbidity 1. Vascular calcification is associated with a worse prognosis after lower limb artery endovascular revascularization: multi-variate analysis reported that the percentage of calcified plaque is an independent predictor of binary restenosis at 12 months 2. Vascular calcification favors plaque rupture and contributes to hypertension depending on its localization and extent. Anatomo-histological studies have shown that atherosclerotic plaque compositions largely differ between anatomical locations in peripheral arterial diseases (PAD). Plaque calcifications are heterogeneous with various types of calcifications, including predominantly microcalcifications in carotid arteries (CA) and bone tissue (osteoid metaplasia) in femoral arteries (FA) 3,4. These differences do not derive from distinct stages of plaque progression , as femoral plaques tend to develop later than those in CA 5. The discrepancies in calcification burden could therefore derive from different shear stress conditions 6 , intrinsic biological differences between vascular cells as suggested by their diverse embryological origins 7,8 , or exposure to different cardiovascular risk factors (CVRF), as CVRF also differentially affect plaque development differentially between arterial beds 9–12 .

Published
2018

6. Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification

Author

Espitia, Olivier, Chatelais, Mathias, Steenman, Marja, Charrier, Céline, Maurel, Blandine, Georges, Steven, Houlgatte, Rémi, Verrecchia, Franck, Ory, Benjamin, Lamoureux, François, Heymann, Dominique, Gouëffic, Yann, Quillard, Thibaut, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôtel-Dieu de Nantes, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Délégation à la Recherche Clinique et à l'Innovation [CHRU Nancy] (DRCI), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Programme Hospitalier de Recherche Clinique (PROG/11/58) to YG. The Fondation de l'Avenir pour la Recherche Médicale Appliquée (ET4-720, http://www.fondationdelavenir.org/) to TQ, the Centre Hospitalier Universitaire de Nantes to TQ, and the Agence Nationale de la Recherche (ANR-16-CE14-0012-01, www.agence-nationale-recherche.fr) to BO. Thibaut Quillard's salary has been provided by the Fondation Lefoulon Delalande (http://lefoulon-delalande.institut-de-france.fr/), the European commission (FP7 People: Marie-Curie Actions, grant 627418, https://ec.europa.eu/research/mariecurieactions/), and the Centre Hospitalier Universitaire de Nantes. Steven George's salary has been provided by the Agence Nationale de la Recherche (ANR-16-CE14-0012-01, www.agence-nationale-recherche.fr)., ANR-16-CE14-0012,EPIBONE,Rôle des protéines à bromodomaines dans la physiologie osseuse normale(2016), European Project: 627418,EC:FP7:PEOPLE,FP7-PEOPLE-2013-IIF,CALTHERO(2014), maurice, sandrine, Comparative Study And Mechanisms Of Calcification Heterogeneity In Atherosclerotic Plaques - CALTHERO - - EC:FP7:PEOPLE2014-07-01 - 2016-06-30 - 627418 - VALID, Hôpital Hôtel-Dieu [Nantes] (Centre Hospitalier Universitaire de Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cell biology, Cell signaling, Physiology, Immune Cells, Immunology, lcsh:Medicine, Signal transduction, Muscle, Smooth, Vascular, Calcification, White Blood Cells, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Animal Cells, Medicine and Health Sciences, Genetics, Humans, lcsh:Science, Aorta, Cells, Cultured, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Blood Cells, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Macrophages, lcsh:R, Biology and Life Sciences, Signaling cascades, Computational Biology, Calcinosis, Cell Differentiation, Arteries, Genomics, Femoral Arteries, Genome Analysis, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Carotid Arteries, TGF-beta signaling cascade, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cardiovascular Anatomy, Blood Vessels, lcsh:Q, Anatomy, Cellular Types, Physiological Processes, Transcriptome, Transcriptome Analysis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

International audience; Vascular calcification is a strong and independent predictive factor for cardiovascular complications and mortality. Our previous work identified important discrepancies in plaque composition and calcification types between carotid and femoral arteries. The objective of this study is to further characterize and understand the heterogeneity in vascular calcifica-tion among vascular beds, and to identify molecular mechanisms underlying this process. We established ECLAGEN biocollection that encompasses human atherosclerotic lesions and healthy arteries from different locations (abdominal, thoracic aorta, carotid, femoral, and infrapopliteal arteries) for histological, cell isolation, and transcriptomic analysis. Our results show that lesion composition differs between these locations. Femoral arteries are the most calcified arteries overall. They develop denser calcifications (sheet-like, nodule), and are highly susceptible to osteoid metaplasia. These discrepancies may derive from intrinsic differences between SMCs originating from these locations, as microarray analysis showed specific transcriptomic profiles between primary SMCs isolated from each arterial bed. These molecular differences translated into functional disparities. SMC from femoral arteries showed the highest propensity to mineralize due to an increase in basal TGFβ sig-naling. Our results suggest that biological heterogeneity of resident vascular cells between arterial beds, reflected by our transcriptomic analysis, is critical in understanding plaque biology and calcification, and may have strong implications in vascular therapeutic approaches.

Published
2018

7. BYL719, a new α-specific PI3K inhibitor: Single administration and in combination with conventional chemotherapy for the treatment of osteosarcoma

Author

Gobin, Bérengère, Huin, Marc Baud', Lamoureux, François, Ory, Benjamin, Charrier, Céline, Lanel, Rachel, Battaglia, Séverine, Rédini, Françoise, Lézot, Frédéric, Blanchard, Frédéric, Heymann, Dominique, Heymann, Dominique, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe LIGUE Nationale Contre le Cancer 2012, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK], and The University of Sheffield [Sheffield, U.K.]

Subjects
vascularization, [SDV.CAN] Life Sciences [q-bio]/Cancer, osteosarcoma, osteoclast, mTOR, osteoblast, [SDV.CAN]Life Sciences [q-bio]/Cancer, PI3K
Abstract

International audience; It has been established that disturbances in intracellular signaling pathways play a considerable part in the oncologic process. Phosphatidylinositol-3-kinase (PI3K) has become of key interest in cancer therapy because of its high mutation frequency and/or gain in function of its catalytic subunits in cancer cells. We investigated the therapeutic value of BYL719, a new specific PI3Kα inhibitor that blocks the ATP site, on osteosarcoma and bone cells. The in vitro effects of BYL719 on proliferation, apoptosis, and cell cycle were assessed in human and murine osteosarcoma cell. Its impact on bone cells was determined using human mesenchymal stem cells (hMSC) and human CD14+ osteoclast precursors. Two different murine preclinical models of osteosarcoma were used to analyze the in vivo biological activities of BYL719. BYL719 decreased cell proliferation by blocking cell cycle in G0/G1 phase with no outstanding effects on apoptosis cell death in HOS and MOS-J tumor cells. BYL719 inhibited cell migration and can thus be considered as a cytostatic drug for osteosarcoma. In murine preclinical models of osteosarcoma, BYL719 significantly decreased tumor progression and tumor ectopic bone formation as shown by a decrease of Ki67+ cells and tumor vascularization. To explore the maximum therapeutic potential of BYL719, the drug was studied in combination with conventional chemotherapeutic drugs, revealing promising efficacy with ifosfamide. BYL719 also exhibited dual activities on osteoblast and osteoclast differentiation. Overall, the present work shows that BYL719 is a promising drug in either a single or multidrug approach to curing bone sarcoma.

Published
2015

8. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.: Additive effect of ZOL and mTOR on osteosarcoma development

Author

Moriceau, Gatien, Ory, Benjamin, Mitrofan, Laura, Riganti, Chiara, Blanchard, Frédéric, Brion, Régis, Charrier, Céline, Battaglia, Séverine, Pilet, Paul, Denis, Marc, Shultz, Leonard, Mönkkönen, Jukka, Rédini, Françoise, Heymann, Dominique, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Massachusetts General Hospital Cancer Center, Harvard Medical School [Boston] (HMS), Department of Pharmaceutics, University of Kuopio, Department of Genetics, Biology and Biochemistry, University of Turin, Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Jackson Laboratory [Bar Harbor] (JAX), and This work was supported by a grant from Pharma Novartis (Rueil-Malmaison, France) and by a NIH Cancer Core grant CA34196.

Subjects
musculoskeletal diseases, MESH: Protein Prenylation, MESH: Cell Line, Tumor, MESH: Humans, MESH: Osteosarcoma, MESH: Rats, MESH: Diphosphonates, MESH: Bone Neoplasms, MESH: Male, MESH: Drug Resistance, Neoplasm, MESH: Drug Synergism, MESH: Bone Density Conservation Agents, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Mice, Inbred C57BL, MESH: Cell Growth Processes, MESH: Animals, MESH: Sirolimus, MESH: Mice, Inbred C3H, MESH: Mice, MESH: ras Proteins, MESH: TOR Serine-Threonine Kinases, MESH: Imidazoles
Abstract

International audience; Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.

Published
2010

9. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.: Additive effect of ZOL and mTOR on osteosarcoma development

Author

Moriceau, Gatien, Ory, Benjamin, Mitrofan, Laura, Riganti, Chiara, Blanchard, Frédéric, Brion, Régis, Charrier, Céline, Battaglia, Séverine, Pilet, Paul, Denis, Marc, Shultz, Leonard, Mönkkönen, Jukka, Rédini, Françoise, Heymann, Dominique, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Massachusetts General Hospital Cancer Center, Harvard Medical School [Boston] (HMS), Department of Pharmaceutics, University of Kuopio, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Jackson Laboratory [Bar Harbor] (JAX), This work was supported by a grant from Pharma Novartis (Rueil-Malmaison, France) and by a NIH Cancer Core grant CA34196., and Heymann, D

Subjects
musculoskeletal diseases, MESH: Protein Prenylation, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Cell Line, Tumor, MESH: Humans, MESH: Osteosarcoma, MESH: Rats, MESH: Diphosphonates, MESH: Bone Neoplasms, MESH: Male, MESH: Drug Resistance, Neoplasm, MESH: Drug Synergism, MESH: Bone Density Conservation Agents, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Mice, Inbred C57BL, MESH: Cell Growth Processes, MESH: Animals, MESH: Sirolimus, MESH: Mice, Inbred C3H, MESH: Mice, MESH: ras Proteins, MESH: TOR Serine-Threonine Kinases, MESH: Imidazoles
Abstract

International audience; Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.

Published
2010

10. Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells

Author

Ory, Benjamin, Moriceau, Gatien, Trichet, Valérie, Blanchard, Frédéric, Berreur, Martine, Rédini, Françoise, Rogers, Michael, Heymann, Dominique, Heymann, D, Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Musculoskeletal Research Programme, University of Aberdeen, Centre hospitalier universitaire de Nantes (CHU Nantes), and This work was supported by INSERM and the Région des Pays de la Loire. Benjamin ORY received a fellowship from INSERM and the Région des Pays de la Loire.

Subjects
bisphosphonate, MESH: Cell Line, Tumor, MESH: Osteosarcoma, MESH: Diphosphonates, MESH: Dose-Response Relationship, Drug, zoledronic acid, MESH: Geranyltranstransferase, MESH: Aged, 80 and over, osteosarcoma, MESH: Cell Proliferation, MESH: RNA, Small Interfering, MESH: Adolescent, MESH: Aged, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Humans, MESH: Middle Aged, MESH: Transfection, MESH: Time Factors, MESH: Adult, MESH: Drug Resistance, Neoplasm, MESH: Male, metabolic resistance, MESH: Cell Survival, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Antineoplastic Agents, farnesyl diphosphate synthase, MESH: Female, MESH: Imidazoles
Abstract

International audience; We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.

Published
2008

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