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.
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cell Rep. 2022 Aug 30;40(9):111253. doi: 10.1016/j.celrep.2022.111253.
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.
KRAS 突变的激活和 SWI/SNF 复合物成员（包括 ARID1A）的功能丧失，在原发性肝肿瘤胆管癌（CC）中同时存在。这些突变如何协同促进 CC 的发生尚未确定。使用肝细胞和胆管特异性谱系追踪的小鼠模型，我们表明 Kras 和 Arid1a 突变驱动了胆管区 CC 和肿瘤前体的形成，而肝炎症加速了这一过程。通过培养细胞，我们发现 Arid1a 的缺失会导致细胞增殖、脱离细胞周期控制、衰老以及染色质结构的广泛改变。值得注意的是，我们表明，由 Kras/Arid1a 合作和 CC 组织损伤引起的胆管增殖反应是由于 TGF-β-Smad4 肿瘤抑制途径的失败激活。因此，我们确定 ARID1A-TGF-β-Smad4 轴对于限制胆管上皮对致癌损伤的反应至关重要，而其缺失则导致胆管前病变和 CC。
