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FAP+ fibroblasts orchestrate tumor microenvironment remodeling in renal cell carcinoma with tumor thrombus

Author

Listed:
  • Jiacheng Ma

    (Tsinghua University
    Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences))

  • Yan Huang

    (Chinese PLA General Hospital)

  • Jie Chen

    (Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences)
    Renmin Hospital of Wuhan University)

  • Yang Li

    (Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences))

  • Rongyan Yao

    (Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences)
    Tsinghua University)

  • Xiubin Li

    (Chinese PLA General Hospital)

  • Qiyang Liang

    (Chinese PLA General Hospital)

  • Xinran Chen

    (Chinese PLA General Hospital)

  • Cheng Peng

    (Chinese PLA General Hospital)

  • Kan Liu

    (Chinese PLA General Hospital)

  • Yuanjun Zhai

    (Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences))

  • Xu Zhang

    (Chinese PLA General Hospital)

  • Xin Ma

    (Chinese PLA General Hospital)

  • Xiaowen Wang

    (Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences))

  • Qingbo Huang

    (Chinese PLA General Hospital)

  • Fuchu He

    (Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences)
    International Academy of Phronesis Medicine (Guangdong))

Abstract

Tumor thrombus (TT) worsens prognosis and complicates surgery in renal cell carcinoma (RCC), yet its formation mechanisms remain unclear. Here, we perform integrative single-cell and spatial transcriptomic analyses on 71 tissues and 48 sections from RCC patients with or without TT. The cellular and spatial atlas reveals distinct TT-associated tumor microenvironment remodeling characterized by the enrichment of FAP+ fibroblasts. These FAP+ fibroblasts are spatially contiguous to aggressive cancer cells and promote their malignant phenotypes in vitro. Their abundance inversely correlates with functional NK cells, suggesting roles in tumor invasion and immune evasion. Furthermore, single-cell multiomics analysis identifies tumor pericytes as a source of FAP+ fibroblasts and delineates transcription factor dynamics underlying pericyte-fibroblast transition. Finally, high levels of FAP+ fibroblasts are associated with poor prognosis and predict a weaker response to anti-VEGF-based therapy. In conclusion, our study highlights FAP+ fibroblasts as drivers of aggressive RCC with TT, suggesting potential therapeutic targets.

Suggested Citation

  • Jiacheng Ma & Yan Huang & Jie Chen & Yang Li & Rongyan Yao & Xiubin Li & Qiyang Liang & Xinran Chen & Cheng Peng & Kan Liu & Yuanjun Zhai & Xu Zhang & Xin Ma & Xiaowen Wang & Qingbo Huang & Fuchu He, 2025. "FAP+ fibroblasts orchestrate tumor microenvironment remodeling in renal cell carcinoma with tumor thrombus," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64447-2
    DOI: 10.1038/s41467-025-64447-2
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