Amplification of R-spondin1 signaling induces granulosa cell fate defects and cancers in mouse adult ovary.
R-spondin1 is a secreted regulator of WNT signaling, involved in both embryonic development and homeostasis of adult organs. It can have a dual role, acting either as a mitogen or as a tumor suppressor. During ovarian development, Rspo1 is a key factor required for sex determination and differentiation of the follicular cell progenitors, but is downregulated after birth. In human, increased RSPO1 expression is associated with ovarian carcinomas, but it is not clear whether it is a cause or a consequence of the tumorigenic process. To address the role of Rspo1 expression in adult ovaries, we generated an Rspo1 gain-of-function mouse model. Females were hypofertile and exhibited various ovarian defects, ranging from cysts to ovarian tumors. Detailed phenotypical characterization showed anomalies in the ovulation process. Although follicles responded to initial follicle-stimulating hormone stimulation and developed normally until the pre-ovulatory stage, they did not progress any further. Although non-ovulated oocytes degenerated, the surrounding follicular cells did not begin atresia. RSPO1-induced expression not only promotes canonical WNT signaling but also alters granulosa cell fate decisions by maintaining epithelial-like traits in these cells. This prevents follicle cells from undergoing apoptosis, leading to the accumulation of granulosa cell tumors that reactivates the epithelial program from their progenitors. Taken together, our data demonstrate that activation of RSPO1 is sufficient in promoting ovarian tumors and thus supports a direct involvement of this gene in the commencement of ovarian cancers.
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.|EA 7310, Université de Corte, Corte, France.
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De Cian
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Pauper
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
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Bandiera
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Vidal
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Sacco
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Gregoire
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Chassot
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Panzolini
Department of Anatomy and Neuroscience, University of Melbourne, Parkville Victoria, Australia.
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Wilhelm
UMR BDR, INRA, ENVA, Université Paris Saclay, Jouy-en-Josas, France.
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Pailhoux
Department of Pathobiology, Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht University, Utrecht, The Netherlands.
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Youssef
Department of Pathobiology, Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht University, Utrecht, The Netherlands.|Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
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de Bruin
Department of Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands.
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Teerds
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Schedl
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Gillot
University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.
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Chaboissier
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006107:Granulosa Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
C518903:RSPO1 protein, mouse; D019699:Thrombospondins