Arid1a mutation suppresses TGF-β signaling and induces cholangiocarcinoma

• DOI: 10.1016/j.celrep.2022.111253
• Publication Date: 2022-08-30T14:30:26Z
• Authors: Bing Guo; Scott C. Friedland; William Alexander; Jacquelyn A. Myers; Wenjia Wang; Michael R. O’Dell; Michael Getman; Christa L. Whitne...; Diana Agostini-Vulaj; Aaron R. Huber; Stephano S. Mello; Paula M. Vertino; Hartmut K. Land; Laurie A. Steiner; Aram F. Hezel
• Keywords: ARID1A

Activating KRAS mutations and functional loss of members the SWI/SNF complex, including ARID1A, are found together in primary liver tumor cholangiocarcinoma (CC). How these cooperate to promote CC has not been established. Using murine models hepatocyte biliary-specific lineage tracing, we show that Kras Arid1a drive formation precursors from biliary compartment, which accelerated by inflammation. cultured cells, find causes cellular proliferation, escape cell-cycle control, senescence, widespread changes chromatin structure. Notably, proliferative response elicited Kras/Arid1a cooperation tissue injury is caused failed engagement TGF-β-Smad4 suppressor pathway. We thus identify an ARID1A-TGF-β-Smad4 axis as essential limiting epithelial oncogenic insults, while its leads pre-neoplasia CC.