Activation of RAS/MEK/ERK signaling drives biliary differentiation in primary liver cancer [112UE]

RAS mutations are frequently observed in human cholangiocarcinoma (CCA), while they are relatively rare in hepatocellular carcinoma (HCC). In a genetically engineered mouse model with liver specific conditional deletion of tumor suppressors Rb and p53 together with activation of oncogenic KRAS, intrahepatic CCA develop primarily from hepatocytes. CCA show activation of PI3K/AKT and MEK/ERK signaling pathways. targeted genetic inactivation of each of these downstream pathways of KRAS leads to delayed tumor growth and profound alterations in tumor differentiation. Specifically, reduced PI3K/AKT signaling promotes the formation of well-differentiated tumors, whereas the inactivation of MEK/ERK signaling induces a differentiation switch towards a more hepatocyte-like phenotype.