ARID1A loss drives gastric signet ring cell carcinoma by regulating mucin production and secretion PMID: 42230634

ADC Targets in Oncology

2026-04-10

ARID1A loss drives gastric signet ring cell carcinoma by regulating mucin production and secretion

Nat Commun. 2026 Jun 2. doi: 10.1038/s41467-026-73933-0.

Hongyu Liu ^# ¹ , Ailing Zhong ^# ¹ , Zhenghao Lu ^# ² ³ , Limin Gao ^# ⁴ , Mengsha Zhang ¹ , Jiaxin Li ¹ , Yingjie Wang ¹ , Yiyun Wang ¹ , Lanxin Zhang ¹ , Jiabo Zhang ¹ , Xiangyu Pan ¹ , Xuelan Chen ¹ , Jingyao Chen ¹ , Siyu He ¹ , Xinyuan Wang ¹ , Xudong Wan ¹ , Xintong Deng ¹ , Tingfa Peng ⁵ , Jian Wang ¹ , Jiajia Du ¹ , Kun Yang ² , Kai Liu ² , Xinzu Chen ² , Xiaolong Chen ² , Zhe Feng ⁶ , Baohong Wu ¹ , Jing Xu ¹ , Linyong Zhao ² , Weihan Zhang ² , Shengyong Yang ¹ , Yuan Wang ¹ , Lu Chen ¹ , Zhihong Xue ¹ , Chengjian Zhao ¹ , Lunzhi Dai ¹ , Feifei Na ⁷ , Jiankun Hu ⁸ , Yu Liu ⁹ , Chong Chen ¹⁰ ¹¹

Affiliations

1. State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
2. Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
3. Chengdu OrganoidMed Medical Laboratory, West China Health Valley, Chengdu, Sichuan, China.
4. Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
5. Department of Gastroenterology, Armed Police Forces Hospital of Sichuan, Chengdu, Sichuan, China.
6. Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
7. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
8. Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
9. State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
10. State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
11. Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan, China. [email protected].
# Contributed equally.

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.