Person: Sarosiek, Kristopher
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Sarosiek
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Kristopher
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Sarosiek, Kristopher
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Publication MEDUSA for Identifying Death Regulatory Genes in Chemo-genetic Profiling Data(MyJove Corporation, 2025-02-07) Honeywell, Megan; Isidor, Marie S.; Fraser, Cameron; Sarosiek, KristopherPublication BCL-XL directly modulates RAS signalling to favour cancer cell stemness(Nature Publishing Group UK, 2017) Carné Trécesson, Sophie de; Souazé, Frédérique; Basseville, Agnès; Bernard, Anne-Charlotte; Pécot, Jessie; Lopez, Jonathan; Bessou, Margaux; Sarosiek, Kristopher; Letai, Anthony; Barillé-Nion, Sophie; Valo, Isabelle; Coqueret, Olivier; Guette, Catherine; Campone, Mario; Gautier, Fabien; Juin, Philippe PaulIn 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.