BCL-XL directly modulates RAS signalling to favour cancer cell stemness

Sophie de Carné Trécesson, Frédérique Souazé, Agnès Basseville, Anne-Charlotte Bernard, Jessie Pécot, Jonathan Lopez, Margaux Bessou, Kristopher A. Sarosiek, Anthony Letai, Sophie Barillé-Nion, Isabelle Valo, Olivier Coqueret, Catherine Guette, Mario Campone, Fabien Gautier and Philippe Paul Juin ()
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Sophie de Carné Trécesson: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Frédérique Souazé: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Agnès Basseville: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Anne-Charlotte Bernard: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Jessie Pécot: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Jonathan Lopez: Service de Biochimie et Biologie moléculaire—Centre Hospitalier Lyon Sud, Faculté de Médecine Lyon Sud—Université Lyon 1, Centre de Recherche en Cancérologie de Lyon—INSERM U1052 CNRS U5286
Margaux Bessou: Service de Biochimie et Biologie moléculaire—Centre Hospitalier Lyon Sud, Faculté de Médecine Lyon Sud—Université Lyon 1, Centre de Recherche en Cancérologie de Lyon—INSERM U1052 CNRS U5286
Kristopher A. Sarosiek: Dana-Farber Cancer Institute, Harvard Medical School
Anthony Letai: Dana-Farber Cancer Institute, Harvard Medical School
Sophie Barillé-Nion: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Isabelle Valo: Biopathology Department, ICO - Centre de Lutte contre le Cancer Paul Papin
Olivier Coqueret: Team 12 ‘Targeted Therapies and Tumor Escape in Colorectal Cancer’, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - Centre de Lutte contre le Cancer Paul Papin
Catherine Guette: Team 12 ‘Targeted Therapies and Tumor Escape in Colorectal Cancer’, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - Centre de Lutte contre le Cancer Paul Papin
Mario Campone: ICO site René Gauducheau, Boulevard Jacques Monod
Fabien Gautier: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721
Philippe Paul Juin: Team 8 “Stress adaptation and tumor escape”, CRCINA - Institut de Recherche en Santé de l’Université de Nantes-Angers - IRT, BP 70721

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait.

Date: 2017
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DOI: 10.1038/s41467-017-01079-1

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