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

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