Carné Trécesson, Sophie deSouazé, FrédériqueBasseville, AgnèsBernard, Anne-CharlottePécot, JessieLopez, JonathanBessou, MargauxSarosiek, KristopherLetai, AnthonyBarillé-Nion, SophieValo, IsabelleCoqueret, OlivierGuette, CatherineCampone, MarioGautier, FabienJuin, Philippe Paul2017-12-062017Carné Trécesson, S. d., F. Souazé, A. Basseville, A. Bernard, J. Pécot, J. Lopez, M. Bessou, et al. 2017. “BCL-XL directly modulates RAS signalling to favour cancer cell stemness.” Nature Communications 8 (1): 1123. doi:10.1038/s41467-017-01079-1. http://dx.doi.org/10.1038/s41467-017-01079-1.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492434In 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.en-USJournal Article2017-12-0610.1038/s41467-017-01079-1