Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. To investigate the cellular origin(s) of this cancer, we determined the effect of PDAC-relevant gene mutations in distinct cell types of the adult pancreas. We show that a subpopulation of Pdx1-expressing cells is susceptible to oncogenic K-Ras-induced transformation without tissue injury, whereas insulin-expressing endocrine cells are completely refractory to transformation under these conditions. However, chronic pancreatic injury can alter their endocrine fate and allow them to serve as the cell of origin for exocrine neoplasia. These results suggest that one mechanism by which inflammation and/or tissue damage can promote neoplasia is by altering the fate of differentiated cells that are normally refractory to oncogenic stimulation.National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant, P30 CA14051)National Institutes of Health (U.S.) (grant 1 PO1 CA117969 01)American Cancer Society (ACS Research Professor)Anna Fuller FundMassachusetts Institute of Technology (Daniel K. Ludwig Foundation Cancer Research Professor)Howard Hughes Medical Institute (Investigator