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Background <p>Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal malignancy, characterized by extensive vascularization and poor prognosis. Early detection markedly improves patient outcomes, and prostate-specific membrane antigen (PSMA, encoded by FOLH1) imaging has recently emerged as a valuable diagnostic tool for ccRCC. However, the cellular source, spatial distribution, and mechanistic contribution of FOLH1 expression within the tumor microenvironment remain poorly understood.</p> Methods <p>We performed an integrative analysis combining multi-regional single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk RNA-seq data. Computational findings were validated using primary patient-derived endothelial cells, in vitro co-culture systems, and an in vivo syngeneic mouse model.</p> Results <p>Integration of 191,906 single cells revealed pronounced spatial remodeling, with FOLH1 expression highly restricted to ECs. Subclustering identified a distinct FOLH1-positive endothelial cell (FOLH1+EC) population that progressively accumulated from normal kidney to tumor-core regions. Pseudotime analysis positioned FOLH1+ECs at terminal differentiation states enriched for PI3K–Akt and focal adhesion signaling. Mechanistically, we validated that FOLH1-overexpressing ECs promote RCC cell proliferation and migration via the APP–CD74 axis. APP or CD74 knockdown abrogated the tumor-promoting effect of FOLH1-overexpressing endothelial cells. Spatial transcriptomics localized FOLH1+ECs in close proximity to RCC nests, where APP and CD74 are colocalized. In a syngeneic mouse model, pharmacological inhibition of PSMA with 2-PMPA significantly suppressed tumor growth and reversed epithelial–mesenchymal transition (EMT) phenotypes. In clinical cohorts, a high FOLH1/endothelial signature (Cluster C1) was associated with angiogenic/EMT pathway activation and worse survival. Independent clinical validation further confirmed that increased endothelial PSMA expression correlates with microvascular invasion and metastatic burden.</p> Conclusion <p>This study identifies and functionally characterizes a FOLH1+ endothelial population that actively reshapes tumor vascular niches via APP–CD74 signaling. Our findings provide a mechanistic basis for endothelial-restricted PSMA expression and offer preclinical proof-of-concept that targeting this axis effectively curbs ccRCC progression.</p>

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Single-cell and spatial multi-omics reveal mechanistic insights of FOLH1+ endothelial cells in clear cell renal cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Li Cheng,
  • Xun Wang,
  • Xuantong Huang,
  • Qiao Liang,
  • Weidong Gan,
  • Jie Gao,
  • Hongqian Guo

摘要

Background

Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal malignancy, characterized by extensive vascularization and poor prognosis. Early detection markedly improves patient outcomes, and prostate-specific membrane antigen (PSMA, encoded by FOLH1) imaging has recently emerged as a valuable diagnostic tool for ccRCC. However, the cellular source, spatial distribution, and mechanistic contribution of FOLH1 expression within the tumor microenvironment remain poorly understood.

Methods

We performed an integrative analysis combining multi-regional single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk RNA-seq data. Computational findings were validated using primary patient-derived endothelial cells, in vitro co-culture systems, and an in vivo syngeneic mouse model.

Results

Integration of 191,906 single cells revealed pronounced spatial remodeling, with FOLH1 expression highly restricted to ECs. Subclustering identified a distinct FOLH1-positive endothelial cell (FOLH1+EC) population that progressively accumulated from normal kidney to tumor-core regions. Pseudotime analysis positioned FOLH1+ECs at terminal differentiation states enriched for PI3K–Akt and focal adhesion signaling. Mechanistically, we validated that FOLH1-overexpressing ECs promote RCC cell proliferation and migration via the APP–CD74 axis. APP or CD74 knockdown abrogated the tumor-promoting effect of FOLH1-overexpressing endothelial cells. Spatial transcriptomics localized FOLH1+ECs in close proximity to RCC nests, where APP and CD74 are colocalized. In a syngeneic mouse model, pharmacological inhibition of PSMA with 2-PMPA significantly suppressed tumor growth and reversed epithelial–mesenchymal transition (EMT) phenotypes. In clinical cohorts, a high FOLH1/endothelial signature (Cluster C1) was associated with angiogenic/EMT pathway activation and worse survival. Independent clinical validation further confirmed that increased endothelial PSMA expression correlates with microvascular invasion and metastatic burden.

Conclusion

This study identifies and functionally characterizes a FOLH1+ endothelial population that actively reshapes tumor vascular niches via APP–CD74 signaling. Our findings provide a mechanistic basis for endothelial-restricted PSMA expression and offer preclinical proof-of-concept that targeting this axis effectively curbs ccRCC progression.