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<p>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 &lt; 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Qiang Sun,
  • Shuxun Wei,
  • Jun Yao,
  • Fuqin Wang,
  • Han Wu,
  • Zunqi Hu,
  • Xin Zhang,
  • Dejun Yang,
  • Weijun Wang,
  • Kai Xu

摘要

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.