Regulation of tumor metastasis and lipid metabolism reprogramming via the CCL5/GGT5 axis in gastric cancer.

Gastric carcinoma (GC) represents a highly invasive and molecularly diverse malignant neoplasm. Within the tumor microenvironment, cancer-associated fibroblasts (CAFs) constitute a critical cellular component of the GC ecosystem, where elevated infiltration densities is correlated with the metastatic ability of the tumor and the progression of the disease in GC patients. Our investigation elucidated the molecular pathway through which CAF-secreted chemokine CCL5 facilitates GC metastatic progression via upregulation of GGT5 expression levels. Utilizing the TCGA-STAD database alongside the GEO dataset (GSE84437), we examined metabolic perturbations characteristic of GC. Through molecular profiling, GC specimens were stratified into three distinct heterogeneous subtypes, wherein Cluster 2 demonstrated inferior prognostic outcomes and more aggressive clinical characteristics. Furthermore, pathway enrichment analyses revealed significant activation of metabolic pathways associated with unsaturated fatty acid biosynthesis and extracellular matrix-related metabolic processes. Through bioinformatics analysis, we identified γ-glutamyltransferase 5 (GGT5), a key enzyme regulating arachidonic acid metabolism. GGT5, an enzyme associated with extracellular matrix remodeling and cell migration, showed high expression in GC. Cytokine flow cytometry results indicated that the expression of CCL5 in the peripheral blood of metastatic GC patients was higher compared to those with gastric carcinoma in situ. We demonstrated that increased extracellular CAF-derived chemokine CCL5 leads to upregulation of GGT5 expression, alterations in EMT-related marker expression, and promotes liver metastasis in nude mice. In conclusion, targeting the CAF-derived chemokine CCL5-mediated GGT5 cascade may provide a novel therapeutic approach for GC.