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Background <p>Gastric cancer (GC) subtypes, particularly diffuse-type GC (DGC) and intestinal-type GC (IGC), exhibit distinct histopathological and microenvironmental features. The molecular mechanisms driving these differences are not fully understood.</p> Methods <p>We integrated bulk transcriptomic data, single-cell RNA sequencing, and spatial transcriptomics to compare IGC and DGC. In vitro and in vivo functional assays were used to investigate the role of the EGR1–IGFBP7/VCAM1 axis.</p> Results <p>Insulin-like Growth Factor Binding Protein 7 (IGFBP7) was predominantly expressed in stromal fibroblasts and endothelial cells in IGC, but additionally in malignant epithelial cells in DGC. Early Growth Response 1 (EGR1) was identified as a key transcriptional co-activator of IGFBP7 and Vascular Cell Adhesion Molecule 1 (VCAM1), defining the EGR1–IGFBP7/VCAM1 axis. This pathway induced endothelial-to-mesenchymal transition (EndMT) and abnormal angiogenesis, generating Cancer-Associated Fibroblast (CAF)-like endothelial derivatives that enhanced epithelial-mesenchymal transition (EMT) in tumor cells. Functional assays showed subtype-specific effects—strongly promoting tumor growth in DGC but potentially inhibiting growth in IGC. In DGC, high axis activity promoted invasion, peritoneal dissemination, resistance to epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), and induced immune exclusion, with expansion of CAFs and M2-like macrophages and reduced CD8⁺T-cell infiltration.</p> Conclusions <p>This study systematically explored the heterogeneity between IGC and DGC, and identified EGR1 as a key participant in EndMT within DGC. We defined the EGR1–IGFBP7/VCAM1 axis as a subtype-dependent regulator linking vascular remodeling, stromal reprogramming, EMT, and immune exclusion, highlighting it as a potential precision therapeutic target, particularly for DGC.</p> Graphical Abstract <p></p>

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Dissecting molecular heterogeneity in primary gastric cancer by IGFBP7-related analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Yuan-jie Liu,
  • Qian-wen Ye,
  • Wei Zhang,
  • Jie-pin Li,
  • Ling-ping Ji,
  • Shen-lin Liu,
  • Xi Zou

摘要

Background

Gastric cancer (GC) subtypes, particularly diffuse-type GC (DGC) and intestinal-type GC (IGC), exhibit distinct histopathological and microenvironmental features. The molecular mechanisms driving these differences are not fully understood.

Methods

We integrated bulk transcriptomic data, single-cell RNA sequencing, and spatial transcriptomics to compare IGC and DGC. In vitro and in vivo functional assays were used to investigate the role of the EGR1–IGFBP7/VCAM1 axis.

Results

Insulin-like Growth Factor Binding Protein 7 (IGFBP7) was predominantly expressed in stromal fibroblasts and endothelial cells in IGC, but additionally in malignant epithelial cells in DGC. Early Growth Response 1 (EGR1) was identified as a key transcriptional co-activator of IGFBP7 and Vascular Cell Adhesion Molecule 1 (VCAM1), defining the EGR1–IGFBP7/VCAM1 axis. This pathway induced endothelial-to-mesenchymal transition (EndMT) and abnormal angiogenesis, generating Cancer-Associated Fibroblast (CAF)-like endothelial derivatives that enhanced epithelial-mesenchymal transition (EMT) in tumor cells. Functional assays showed subtype-specific effects—strongly promoting tumor growth in DGC but potentially inhibiting growth in IGC. In DGC, high axis activity promoted invasion, peritoneal dissemination, resistance to epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), and induced immune exclusion, with expansion of CAFs and M2-like macrophages and reduced CD8⁺T-cell infiltration.

Conclusions

This study systematically explored the heterogeneity between IGC and DGC, and identified EGR1 as a key participant in EndMT within DGC. We defined the EGR1–IGFBP7/VCAM1 axis as a subtype-dependent regulator linking vascular remodeling, stromal reprogramming, EMT, and immune exclusion, highlighting it as a potential precision therapeutic target, particularly for DGC.

Graphical Abstract