ARID1A Stimulates Notch-TLL1 Signaling to Induce Cancer-Associated Fibroblast Activation and Intrahepatic Cholangiocarcinoma Development
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.
Authors
- Shuqun Cheng (ORCID: https://orcid.org/0000-0001-6760-7470)
- Qian‐Wen Zheng
- Xiang Wang (ORCID: https://orcid.org/0000-0003-0440-6203)
- Lingyun Long (ORCID: https://orcid.org/0000-0002-8064-832X)
- Yan Ling Chen
- Feng-Kun Zhang
- Jing‐Jing Li (ORCID: https://orcid.org/0000-0002-3973-5405)
- Xiaosong Qiu
- Yan‐Jun Xiang (ORCID: https://orcid.org/0000-0002-7378-6724)
- Hui‐Jun Cao
- Qian‐Zhi Ni (ORCID: https://orcid.org/0000-0002-4659-7696)
- Xin Liang (ORCID: https://orcid.org/0009-0000-0072-8366)
- Wei Chen (ORCID: https://orcid.org/0000-0002-0399-6216)
- Ning Ma (ORCID: https://orcid.org/0000-0003-1825-8854)
- Kai Ding (ORCID: https://orcid.org/0009-0008-4304-4333)
- Jing-Yi Huang
- Sheng Xu (ORCID: https://orcid.org/0009-0004-5664-8372)
- Yu Chen (ORCID: https://orcid.org/0009-0002-6247-1417)
- Ji Xia (ORCID: https://orcid.org/0000-0001-6228-1096)
- Bing Zhu (ORCID: https://orcid.org/0009-0001-7162-7420)
- Yikang Wang (ORCID: https://orcid.org/0009-0006-3420-7378)
- Chao Song (ORCID: https://orcid.org/0009-0005-2742-4254)
- Kang Wang (ORCID: https://orcid.org/0009-0009-6524-5782)
Institutions
- St. Jude Children's Research Hospital (US)
- Second Military Medical University (CN)
- Fudan University (CN)
- Shanghai Chest Hospital (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Shanghai Ninth People's Hospital (CN)
- Tongde Hospital of Zhejiang Province (CN)
- Shanghai Institute of Applied Physics (CN)
- Zhongshan Hospital (CN)
- Shanghai First People's Hospital (CN)
- Eastern Hepatobiliary Surgery Hospital (CN)
- Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1158/0008-5472.can-25-5082
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00