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Dual roles of ARID1A in both mucin production and secretion suggest susceptibilities of gastric signet ring cell carcinoma [ATAC-Seq]

ABSTRACT: Signet ring cell carcinoma (SRCC) is a lethal malignancy with distinctive histologic features, characterized by mucin-enriched vacuoles in the cytoplasm and compressed nuclei. Gastric SRCC is the most common form of SRCC with increasing incidence in recent years. However, the driver genes of SRCC and the molecular mechanisms underlying its unique morphology remain poorly understood. Here, we report that AT-rich interactive domain-containing protein 1A (ARID1A), one of the most frequently mutated genes in SRCC is a bona fide tumor suppressor gene in gastric SRCC. Its loss, together with Trp53 and Pten loss, drove a SRCC in mice. Mechanistically, Arid1a loss upregulates the expressions of mucins mediated by the BRD9-containing ncBAF complex, which would compete with the ARID1A-containing cBAF complex. And Arid1a can directly regulates the expression of Scin, which is responsible for mucins. And inhibition of Brd9 can ameliorate the malignancy of SRCC. Thus, our study revealed dual roles of ARID1A in restraining SRCC by regulating both mucin production and secretion, providing new mechanistic insights and potential therapeutic vulnerabilities for ARID1A-deficient SRCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE232291 | GEO | 2024/09/18

REPOSITORIES: GEO

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Dual roles of ARID1A in both mucin production and secretion suggest susceptibilities of gastric signet ring cell carcinoma [CUT&Tag]

Project description:Signet ring cell carcinoma (SRCC) is a lethal malignancy with distinctive histologic features, characterized by mucin-enriched vacuoles in the cytoplasm and compressed nuclei. Gastric SRCC is the most common form of SRCC with increasing incidence in recent years. However, the driver genes of SRCC and the molecular mechanisms underlying its unique morphology remain poorly understood. Here, we report that AT-rich interactive domain-containing protein 1A (ARID1A), one of the most frequently mutated genes in SRCC is a bona fide tumor suppressor gene in gastric SRCC. Its loss, together with Trp53 and Pten loss, drove a SRCC in mice. Mechanistically, Arid1a loss upregulates the expressions of mucins mediated by the BRD9-containing ncBAF complex, which would compete with the ARID1A-containing cBAF complex. And Arid1a can directly regulates the expression of Scin, which is responsible for mucins. And inhibition of Brd9 can ameliorate the malignancy of SRCC. Thus, our study revealed dual roles of ARID1A in restraining SRCC by regulating both mucin production and secretion, providing new mechanistic insights and potential therapeutic vulnerabilities for ARID1A-deficient SRCC.

2024-09-18 | GSE232289 | GEO

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Protein profiling reveals the characteristic changes of complement cascade pathway in the tissues of gastric signet ring cell carcinoma

Project description:Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared to adenocarcinomas (ACs). Lacking of systematically molecular overview to this disease made a slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumor and adjacency including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate cellular heterogeneity of the tissues. Proteome of tissues were profiled by data independent acquisition (DIA) mass spectrometry (MS). Based on the over 6 000 proteins quantified. Univariate analysis and pathway enrichment revealed that some proteins and pathways bared the differences between SRCC and ACs. Importantly, the up regulation for a majority of complement-related proteins were iconic for SRCC but not for AC. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, while the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to seek appropriate cell models for gastric SRCC, through proteomic comparison of the 15 gastric cell lines and the gastric tumors. The prediction of supervised classifier suggested none of these gastric cell lines qualified in mimicking SRCC. This study discovered that complement cascade is activated at a higher level in gastric SRCC than AC.

2021-02-25 | PXD022952 | Pride

Protein profiling reveals the characteristic changes of complement cascade pathway in the tissues of gastric signet ring cell carcinoma

2021-02-25 | PXD022405 | Pride

Protein profiling reveals the characteristic changes of complement cascade pathway in the tissues of gastric signet ring cell carcinoma

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Patient-derived Organoids and Xenografts Uncover Therapeutic Vulnerabilities in Colorectal Signet Ring Cell Carcinomas

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2025-01-25 | GSE253804 | GEO

Deep Visual Proteomics reveals DNA replication stress as a hallmark of Signet Ring Cell Carcinoma

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2025-05-07 | PXD053079 | Pride

Ruminococcus torques is a keystone degrader of intestinal mucin glycoprotein, releasing oligosaccharides used by Bacteroides thetaiotaomicron

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