ARID1A Stimulates Notch-TLL1 Signaling to Induce Cancer-Associated Fibroblast Activation and Intrahepatic Cholangiocarcinoma Development

Abstract Intrahepatic cholangiocarcinoma (ICC) is a lethal hepatic malignancy characterized by a prominent desmoplastic stroma. In this study, we demonstrated that AT-rich interactive domain-containing protein 1A (ARID1A), a core component of the Switch/Sucrose (SWI/SNF) protein complex, is upregulated in ICC and plays an oncogenic role. Mechanistically, ARID1A stabilized NICD1 protein by inhibiting AMPK-dependent autophagy and lysosomal degradation, thereby sustaining Notch signaling. Tolloid-like 1 (TLL1), a metalloproteinase that promotes collagen maturation, was found to be a downstream effector of ARID1A/Notch signaling. Specifically, TLL1 derived from ICC cells activated hepatic stellate cells (HSC) and thus promoted tumor progression. Accordingly, ablation of TLL1 attenuated cancer-associated fibroblast infiltration, collagen accumulation, and tumor progression. Moreover, virtual screening of a bioactive compound library identified acarbose, an effective medicine for glycemic control, as a potent inhibitor of TLL1. Pharmacologic inhibition of TLL1 with acarbose suppressed HSC activation, collagen deposition, and tumor development. Collectively, these results establish a tumor-promoting ARID1A–Notch–TLL1 axis in ICC and reveal acarbose as a potential precision therapy for patients with ARID1A-high ICC. Significance: The ARID1A-Notch-TLL1 axis promotes hepatic stellate cell activation and intrahepatic cholangiocarcinoma development, which can be targeted with acarbose as a TLL1 inhibitor to suppress tumor progression.