LMS Seminar- Dr Oscar Fernandez-Capetillo
Rescuing RAS deficiency in mammalian cells
Frequently altered in cancer, RAS proteins are central transducers of growth factor signaling. We have now used mouse embryonic stem cells (mESC) as a model to understand the consequences of RAS deficiency in mammalian cells. Our data reveal that the loss of all RAS genes reduces, but does not prevent, the proliferation rates of mESC, and fully prohibits their differentiation. Strikingly, deletion of ERF, a repressor from the ETS-family of transcription factors, rescues proliferation and differentiation of RAS-less mESC. Moreover, we show that ERF deficiency enables the generation of RAS-devoid teratomas, this being the first example of a tumor that can evolve in the absence of RAS proteins. Finally, we also show recurrent ERF losses in cancer, where this increases the resistance to the pharmacological inhibition of the RAS pathway. In summary, we will present our findings on how cells can tolerate the absence of RAS oncogenes, and the implications this might have for our strategies to target RAS-driven tumors.