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

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.
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Submitted on : Friday, November 3, 2017 - 11:40:06 AM
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Sophie de Carné Trécesson, Frédérique Souazé, Agnes Basseville, Anne-Charlotte Bernard, Jessie Pécot, et al.. BCL-XL directly modulates RAS signalling to favour cancer cell stemness.. Nature Communications, Nature Publishing Group, 2017, 8 (1), pp.1123. ⟨10.1038/s41467-017-01079-1⟩. ⟨inserm-01628330⟩



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