Kras and Tp53 mutations cause cholangiocyte- and hepatocyte-derived cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA with intermediates along this spectrum. Here we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BillN). By contrast, adult hepatocytes were relatively refractory to these mutations and formed rare hepatocellular carcinomas (HCC). In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing towards distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced reprogramming of hepatocytes to biliary cells, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.

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