CAF-enriched COL4A6 promotes gastric cancer progression and stromal remodeling despite an inverse association in bulk transcriptomes

The progression of gastric cancer (GC) is profoundly influenced by extracellular matrix (ECM) remodeling within the tumor microenvironment (TME); however, the compartment-specific roles of key ECM proteins (e.g., epithelium vs. stroma) remain incompletely understood. By integrating multi-omics bulk transcriptomic data with single-cell sequencing data, we observed a bulk-compartment discrepancy for COL4A6: COL4A6 carries an inverse association (OR < 1) in bulk transcriptome-based risk models, whereas its protein is markedly upregulated and predominantly localized to the CAF compartment in clinical specimens. We constructed a Matrisome Risk Score (MRS) model and identified ECM subtypes with distinct prognoses, confirming that the high-matrix subtype (MC1) is closely associated with immunosuppression and chemotherapy resistance. Functional experiments demonstrated that COL4A6 from CAF-enriched fibroblast cultures promotes tumor progression and stromal remodeling by inducing CAF activation (upregulation of α-SMA and FAP, remodeling of stress fibers) and promoting EMT in gastric cancer cells. Collectively, our findings support a compartment-dependent model in which epithelial silencing/loss may bias bulk mRNA associations, whereas CAF-compartment COL4A6 accumulation is a functional driver of GC progression. This highlights CAF-compartment COL4A6 as a potential target for therapies aimed at ECM remodeling within the TME.