Abstract
Signet ring cell carcinoma (SRCC) is a lethal malignancy with distinct histologic features, characterized by accumulated mucins in the cytoplasm which compress nuclei. Gastric SRCC is the most common SRCC whose incidence is increasing in recent years. The molecular mechanisms underlying the histopathology remain poorly understood. Here, we report that AT-rich interactive domain-containing protein 1 A (ARID1A), one of the most frequently mutated genes in gastric SRCC, functions as a bona fide tumor suppressor. Its loss, together with Trp53 and Pten loss, drives SRCC in mice. Mechanistically, Arid1a loss upregulates the expressions of mucins through the competing BRD9-containing ncBAF complex. And mucin secretion is impaired by the downregulation of Scin, a direct target of Arid1a in SRCC. Inhibition of Brd9 ameliorates the malignancy of SRCC. Thus, our study reveals dual roles of ARID1A in both mucin production and secretion, providing new mechanistic insights and potential therapeutic vulnerabilities in SRCC.
Acknowledgements
We thank Dr. Yuquan Wei for generous support. We thank all the CC-LY lab members and Fangfang Wang (Institute of Hematology, West China Hospital) for discussion and technical support. We thank the Core Facilities of West China Hospital and the Chengdu OrganoidMed Medical Laboratory for technical support.
Funding
This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0500500 [Y.L.]); the National Natural Science Foundation of China (T2221004 [C.C.], 82330087 [C.C.], 2024YFF0507400 [C.C.], 82130007 [Y.L.], 82170171 [C.C.], 82470188 [Y.L.], 82300186 [B.W.], 82500226 [J.X]); the Sichuan Science and Technology Program (2025NSFTD0030 [Y.L.], 2025ZNSFSC0047 [C.C.]); the Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation (TFJC2023010004 [C.C.]); the Post-Doctor Research Project, West China Hospital, Sichuan University (2024HXBH179 [J.Z.], 2025HXBH025 [H.L.]); the China Postdoctoral Science Foundation (2023TQ0226 [B.W.]); the From 0 to 1 innovative research project of Sichuan University (2023SCUH0070 [Q.Z.]); Natural Science Foundation of Sichuan Province of China (2024NSFSC1696 [J.X]).
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Liu, H., Zhong, A., Lu, Z. et al. ARID1A loss drives gastric signet ring cell carcinoma by regulating mucin production and secretion. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73933-0
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DOI: https://doi.org/10.1038/s41467-026-73933-0
