Contributors: Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM); Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T); Institut Pasteur de Lille; Pasteur Network (Réseau International des Instituts Pasteur)-Pasteur Network (Réseau International des Instituts Pasteur)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS); Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL); Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome (UCBM); Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); College of Veterinary Medicine Colombus; The Ohio State University Columbus (OSU); Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN); Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon); Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM); Université de Liège = University of Liège = Universiteit van Luik = Universität Lüttich (ULiège); University of Toronto; This work was supported by the Association pour la recherche sur les tumeurs de la prostate (ARTP), the National Center for Scientific Research (CNRS) to EB and by the National Institute of Health and Medical Research (INSERM) and the University of Lyon1. AF was supported by the Ligue nationale contre le cancer and the Fondation pour la recherche médicale (FRM), MB, MG by the French National Cancer Institute (INCa), CD by the Institut Pasteur/Région Nord-Pas-de-Calais, GV by the Labex DEVweCAN and AB from the Belgian National Fund for Scientific Research. CK is a recipient of the H2020 Marie Sklodowska-Curie Individual Fellowship under agreement number (655777-miROMeS).; We are grateful to the Animalerie Lyon Est Conventionnelle (ALECS) and to D. Sahay for discussion.
نبذة مختصرة : International audience ; Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events.
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