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.
Sun et al. (Tue,) studied this question.