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A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth
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Integrated Transcriptomic Analysis and Machine Learning Identify THY1 as a Key Regulator of Cancer-Associated
Sihui Hou1, Mengzhu Sang1, Yan Wang1
1Department of Gastroenterology, Xuzhou Central Hospital, Southeast University, Xuzhou, Jiangsu Province, China.
Background:
Heterogeneity in cancer-associated fibroblast (CAF) infiltration within the tumor microenvironment is closely associated with gastric cancer progression and immune evasion; however, precise CAF-related diagnostic markers and actionable therapeutic targets remain scarce.
Methods:
Weighted gene coexpression network analysis (WGCNA) was employed to screen CAF-related coexpression modules. Gastric cancer samples were stratified into molecular subtypes via nonnegative matrix factorization (NMF). Core genes were screened using LASSO regression, SVM-RFE, and RF. Functional assays (Western blot, CCK-8, colony formation, Transwell, tube formation, ELISA, and flow cytometry) were conducted to assess THY1's role in CAF activation and effects on tumor/immune cells.
Results:
WGCNA identified modules correlated with CAF abundance, yielding 417 hub genes. NMF classified gastric cancer into two molecular subtypes with distinct differences in immune microenvironment, drug sensitivity, and pathway activity. Four core genes (THY1, VASH1, CHSY3, and CDH11) were consistently identified. The nomogram model demonstrated strong diagnostic performance for discriminating gastric cancer from normal tissue (AUC = 0.907 in the discovery cohort and > 0.85 in the validation cohort), with calibration and decision curve analysis (DCA) supporting clinical utility. THY1 knockdown in CAFs downregulated activation markers. Conditioned medium of THY1-deficient CAFs reduced cell proliferation and invasion, inhibited HUVEC tube formation, enhanced CD8+ T cell-mediated tumor killing, and elevated IFN-γ secretion.
Conclusion:
CAF-derived THY1 promoted malignant phenotypes and immune evasion by modulating CAF function and paracrine cross talk with tumor cells, endothelial cells, and CD8+ T cells, offering new insights for tumor microenvironment-targeted therapy in gastric cancer.
