RNA-seq of mouse cell lines isolated from genetically engineered mouse models of extrahepatic cholangiocarcinoma and pancreatic cancer. RNA-seq of mouse cell lines isolated from genetically engineered mouse models of extrahepatic cholangiocarcinoma and pancreatic cancer

Biliary tract cancer (BTC) ranks among the most lethal human malignancies, thereby representing an unmet clinical need. In this study, we find that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible towards transformation by activated Pik3caH1047R, but completely refractory to oncogenic KrasG12D. Using genome-wide in vivo piggyBac transposon-based forward genetic screening and genetic loss-of-function experiments, we discover important extrahepatic cholangiocarcinoma (ECC) cancer genes and find that PI3K-signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts the pancreas, where oncogenic Kras in concert with Trp53 loss of function are key cancer drivers. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development, and bypasses oncogene-induced senescence without triggering the Trp53 pathway. These studies provide a mechanistic link between PI3K-signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor-subtype.