Abstract
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.
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Acknowledgements
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.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.
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Raveux, A., Stedman, A., Coqueran, S. et al. Compensation between Wnt-driven tumorigenesis and cellular responses to ribosome biogenesis inhibition in the murine intestinal epithelium. Cell Death Differ 27, 2872–2887 (2020). https://doi.org/10.1038/s41418-020-0548-6
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DOI: https://doi.org/10.1038/s41418-020-0548-6
