Cooperative pro-tumorigenic adaptation to oncogenic RAS through epithelial to mesenchymal plasticity
Description
In breast cancers, aberrant activation of the RAS/MAPK pathway is strongly associated with mesenchymal features and stemness traits, suggesting an interplay between this mitogenic signaling pathway and epithelial-mesenchymal plasticity (EMP). By using inducible models of human mammary epithelial cells, we demonstrate herein that the oncogenic activation of RAS promotes ZEB1-dependent EMP, which is necessary for malignant transformation. Notably, EMP is triggered by the secretion of pro-inflammatory cytokines from neighboring RAS-activated senescent cells, with a prominent role for IL-6 and IL-1. Our data contrast with the common view of cellular senescence as a tumor suppressive mechanism and EMP as a process promoting late stages of tumor progression in response to signals from the tumor microenvironment. Indeed, we highlighted here a pro-tumorigenic cellular cooperation of RAS-activated mammary epithelial cells, which leverages on oncogene-induced senescence and EMP to trigger cellular reprogramming and tumor initiation.