Arid1a deficiency promotes hepatocyte hyperpolyploidy and drives intrahepatic cholangiocarcinoma in mice

Abstract

Background & Aims: Intrahepatic cholangiocarcinomas (ICCs) are aggressive liver tumors with high heterogeneity and limited therapeutic options. Although traditionally thought to arise from biliary cells, recent findings suggest that hepatocytes may also serve as a cellular origin for ICC. However, the mechanisms underlying hepatocyte malignant transformation and ICC initiation remain poorly understood. Approach and Results: We employed oncogene-driven and chemically induced ICC murine models, along with cellular models, to recapitulate the transformation of hepatocytes into ICC. Our findings demonstrate that mature hepatocytes undergo a significant hyperpolyploid state during ICC initiation. Hyperpolyploidy promotes aberrant cell division and chromosomal instability, accelerating hepatocyte transformation and ICC onset. Furthermore, we identified the chromatin remodeling factor Arid1a as a critical suppressor of hyperpolyploidy. Arid1a deficiency disrupts mitotic machinery at the centrosome, driving hyperpolyploidization and ICC tumorigenesis. Conclusions: Hepatocytes can transform into ICC through a process involving hyperpolyploidizaiton. This study offers new insights into the pathogenesis of ICC, particularly in patients harboring frequent ARID1A mutations.