2. Academic Validation
  3. Arid1a mutation suppresses TGF-β signaling and induces cholangiocarcinoma

Arid1a mutation suppresses TGF-β signaling and induces cholangiocarcinoma

  • Cell Rep. 2022 Aug 30;40(9):111253. doi: 10.1016/j.celrep.2022.111253.
Bing Guo 1,  Scott C Friedland 2,  William Alexander 2,  Jacquelyn A Myers 3,  Wenjia Wang 1,  Michael R O'Dell 4,  Michael Getman 5,  Christa L Whitney-Miller 6,  Diana Agostini-Vulaj 6,  Aaron R Huber 6,  Stephano S Mello 2,  Paula M Vertino 2,  Hartmut K Land 1,  Laurie A Steiner 5,  Aram F Hezel 7
Affiliations

Affiliations

  • 1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, 300 Elmwood Avenue, Rochester, NY 14642, USA.
  • 2 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 3 Genomics Research Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 4 Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, 300 Elmwood Avenue, Rochester, NY 14642, USA.
  • 5 Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 6 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 7 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, 300 Elmwood Avenue, Rochester, NY 14642, USA. Electronic address: aram_hezel@urmc.rochester.edu.
PMID: 36044839 DOI: 10.1016/j.celrep.2022.111253
Abstract

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

Keywords

ARID1A; ATAC-seq; CP: Cancer; KRAS; RNA-seq; TGF-β; bile ducts; cell cycle; cholangiocarcinoma; mouse embryonic fibroblasts; transdifferentiation.

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