Cortactin facilitates malignant transformation of dysplastic cells in gastric cancer development.

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-03-05 DOI:10.1016/j.jcmgh.2025.101490

Alexis A Guenther, Suyeon Ahn, Jimin Min, Changqing Zhang, Hyuk-Joon Lee, Han-Kwang Yang, Bong Hwan Sung, Alissa M Weaver, Eunyoung Choi

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引用次数: 0

Abstract

Background & aims: Epithelial cancer onset occurs through sequential stages of cell lineage conversion and functional dysregulation. Dysplasia is a precancerous lesion defined as a direct precursor to cancer and is histologically defined as a transition stage between pre-cancer and cancer, but molecular and biological mechanisms controlling its transformation to malignancy are underdetermined. Here, we discover the crucial role of the actin stabilization and exosome secretion-regulatory protein cortactin in dysplastic cell transformation to adenocarcinoma.

Methods: We engineered a CRISPR/Cas9-based cortactin knock-out (KO) dysplasia organoid model established from dysplastic tissue and examined malignant roles of cortactin during gastric cancer development in vitro and in vivo.

Results: While dysplastic cell identity remained unchanged, the cortactin KO organoids exhibited a decrease in cellular organization and multicellular protrusions, which are considered aggressive features when observed in vitro. When injected into the flank of nude mice, cortactin KO cells failed malignant transformation into adenocarcinoma and solid tumor formation with reduced recruitment of fibroblasts and macrophages. In addition, cortactin KO cells showed diminished exosome secretion levels and adenocarcinoma development was impaired when exosome secretion was inhibited in cortactin WT dysplastic cells.

Conclusions: These data suggest that cortactin is a functional element of membrane dynamics, malignant changes, and exosome secretion in dysplastic cells, and solid gastric tumor formation associated with alteration of the tumor microenvironment.

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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.