Cortactin Facilitates Malignant Transformation of Dysplastic Cells in Gastric Cancer DevelopmentSummary
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, b...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000311 |
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| Summary: | 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: Although 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 wild-type 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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| ISSN: | 2352-345X |