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. Here, we demonstrated that ARID1A, a core component of the 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. 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 (HSCs) and thus promoted tumor progression. Accordingly, ablation of TLL1 attenuated cancer-associated fibroblast (CAF) 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 for TLL1. Pharmacological 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 ARID1A-high ICC patients.