Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16INK4A induction. Moreover, the KRas-Twist-p16INK4A senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.
Highlights
► Oncogenic KRas abrogates premature senescence of pancreatic ductal cells ► Senescence bypass is executed via Twist-dependent suppression of p16INK4A expression ► Inflammatory stress triggers a p16INK4A-dependent senescence of ductal cells in vivo ► Oncogenic KRas suppresses inflammation-induced senescence in vivo
