Interplay among oncogenic pathways governs hepatobiliary lineage decisions in liver cancer

Although hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and combined HCC–CCA have long been regarded as distinct pathological entities, accumulating evidence from lineage tracing, genomics and transcriptomics increasingly supports the concept that liver cancers exist along a hepatobiliary continuum. The emergence of shared molecular subclasses between HCC and intrahepatic cholangiocarcinoma (iCCA) underscore the remarkable plasticity of liver epithelial cells. This evolving framework is essential when interpreting studies on lineage conversion, including the recent work by Rösner et al., who report that RAS/MEK/ERK activation drives robust biliary differentiation from hepatocytes.