1. Compensation between Wnt-driven tumorigenesis and cellular responses to ribosome biogenesis inhibition in the murine intestinal epithelium
- Author
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Sabrina Coqueran, Aurélien Raveux, Béatrice Romagnolo, Michel Cohen-Tannoudji, Sandrine Vandormael-Pournin, Aline Stedman, Nick D.L. Owens, Embryon précoce de mammifères et cellules souches, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège doctoral [Sorbonne universités], Sorbonne Université (SU), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epigénétique des Cellules Souches - Epigenetics of Stem Cells, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Fondation ARC pour le Recherche sur le cancer (PGA120140200873), the Institut Pasteur, the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche (ANR-10-LABX-73-01 REVIVE) and the Institut National du Cancer (INCa 2007-1-COL-6-IC-1 and PLBIO09-070). A.R. was supported by the Université Pierre et Marie Curie and received fellowship from the French Ministère de l’Enseignement Supérieur et de la recherche, the Fondation ARC pour la Recherche sur le Cancer and the REVIVE Labex. AS received support from the Fondation des Treilles., Imaging analyses was performed at the Imagopole and the histopathology Unit of the Institut Pasteur. We are grateful to the staff of the animal facility of Institut Pasteur for animal care and their help during this work. We thank G. Comai for technical help and advices on RNAscope ISH., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège Doctoral, Laboratoire de Biologie du Développement [IBPS] (LBD), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Adenomatous Polyposis Coli Protein ,Ribosome biogenesis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Intestinal Mucosa ,Progenitor cell ,Wnt Signaling Pathway ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Molecular Biology ,Organelle Biogenesis ,Wnt signaling pathway ,Membrane Proteins ,Cell Biology ,Cell cycle ,Wnt signaling ,Colorectal cancer ,Intestinal epithelium ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics ,Cell Transformation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Stem cell ,Carcinogenesis ,Ribosomes - Abstract
International audience; Ribosome biogenesis inhibition causes cell cycle arrest and apoptosis through the activation of tumor suppressor-dependent surveillance pathways. These responses are exacerbated in cancer cells, suggesting that targeting ribosome synthesis may be beneficial to patients. Here, we characterize the effect of the loss-of-function of Notchless (Nle), an essential actor of ribosome biogenesis, on the intestinal epithelium undergoing tumor initiation due to acute Apc loss-of-function. We show that ribosome biogenesis dysfunction strongly alleviates Wnt-driven tumor initiation by restoring cell cycle exit and differentiation in Apc-deficient progenitors. Conversely Wnt hyperactivation attenuates the cellular responses to surveillance pathways activation induced by ribosome biogenesis dysfunction, as proliferation was maintained at control-like levels in the stem cells and progenitors of double mutants. Thus, our data indicate that, while ribosome biogenesis inhibition efficiently reduces cancer cell proliferation in the intestinal epithelium, enhanced resistance of Apc-deficient stem and progenitor cells to ribosome biogenesis defects may be an important concern when using a therapeutic strategy targeting ribosome production for the treatment of Wnt-dependent tumorigenesis.
- Published
- 2020