Combination of Kras activation and PTEN deletion contributes to murine hepatopancreatic ductal malignancy

Kras mutations are among the most common genetic abnormalities in human neoplasms, including cholangiocarcinomas, pancreatic cancer and colon cancer. PTEN has previously been associated with cholangiocarcinoma development in murine models. Here, we have established novel mouse models of neoplasms by liver-specific and biliary-pancreatic Kras activation and PTEN deletion. By liver-specific disruption of PTEN and activation of Kras in mice caused rapid development of intrahepatic biliary epithelial proliferative lesions (Intrahepatic cholangiocarcinoma, ICC), which progress through dysplasia to invasive carcinoma. In contrast, Kras activation in combination with heterozygous PTEN deletion induced mixed carcinomas of liver (both ICC and hepatocellular carcinoma, HCC), whereas Kras activation alone did not induce biliary tract neoplasm. Use of Sox9-Cre-LoxP-based approach to coordinately delete PTEN and activate Kras in the adult mouse resulted in not only development of low-grade biliary lesions (ICC and extrahepatic bile duct carcinoma, ECC) but also pancreatic carcinomas. Our data provide a functional link between PTEN gene status, hepatobiliary cell fate, and HCC, biliary carcinoma, pancreatic cancer pathogenesis, and present novel genetically engineered mouse models of PTEN loss-driven malignancy.