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Background <p>Colorectal cancer (CRC) is a common gastrointestinal cancer with poor response to therapy and high metastatic risk. Cancer-associated fibroblasts (CAFs) support tumor progression, but their functional heterogeneity remains poorly understood.</p> Methods <p>We integrated multi-omics data from 10,164 samples, including single-cell, bulk, spatial transcriptomics, and proteomics, to identify and characterize CAF subpopulations. Functional validation was performed using molecular assays, in vivo models, and drug screening.</p> Results <p>We identified a COL10A1-positive fibroblast subpopulation (COL10A1<sup>+</sup>Fib) associated with CRC progression and poor patient prognosis. COL10A1<sup>+</sup>Fib promotes tumor cell proliferation, immune suppression, and metastasis. Mechanistically, COL10A1<sup>+</sup>Fib facilitates epithelial–mesenchymal transition (EMT) in CRC cells via COL10A1 secretion and induces M2 macrophage polarization through the COL10A1/CD18/JAK1/STAT3 signaling axis. In turn, M2 macrophages enhance COL10A1 expression in fibroblasts via the TGF-β/RUNX2 pathway, forming a pro-tumorigenic feedback loop. The DNA-PKcs inhibitor NU7441 reduces COL10A1 expression, suppresses CAF activity, and reverses EMT and M2 polarization. Pan-cancer analysis suggests that COL10A1<sup>+</sup>Fib may have similar functional roles across multiple major solid tumors.</p> Conclusion <p>Our study identifies a CAF subpopulation, COL10A1<sup>+</sup>Fib, associated with CRC progression and immune suppression, suggesting it as a potential therapeutic target in CRC and possibly other malignancies.</p>

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COL10A1+ fibroblasts promote colorectal cancer metastasis and M2 macrophage polarization with pan-cancer relevance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月18日

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  • Shangshang Hu,
  • Muzi Ding,
  • Jinwei Lou,
  • Jian Qin,
  • Yuhan Chen,
  • Zixuan Liu,
  • Yue Li,
  • Junjie Nie,
  • Mu Xu,
  • Huiling Sun,
  • Xinliang Gu,
  • Tao Xu,
  • Shukui Wang,
  • Shukui Wang,
  • Yuqin Pan

摘要

Background

Colorectal cancer (CRC) is a common gastrointestinal cancer with poor response to therapy and high metastatic risk. Cancer-associated fibroblasts (CAFs) support tumor progression, but their functional heterogeneity remains poorly understood.

Methods

We integrated multi-omics data from 10,164 samples, including single-cell, bulk, spatial transcriptomics, and proteomics, to identify and characterize CAF subpopulations. Functional validation was performed using molecular assays, in vivo models, and drug screening.

Results

We identified a COL10A1-positive fibroblast subpopulation (COL10A1+Fib) associated with CRC progression and poor patient prognosis. COL10A1+Fib promotes tumor cell proliferation, immune suppression, and metastasis. Mechanistically, COL10A1+Fib facilitates epithelial–mesenchymal transition (EMT) in CRC cells via COL10A1 secretion and induces M2 macrophage polarization through the COL10A1/CD18/JAK1/STAT3 signaling axis. In turn, M2 macrophages enhance COL10A1 expression in fibroblasts via the TGF-β/RUNX2 pathway, forming a pro-tumorigenic feedback loop. The DNA-PKcs inhibitor NU7441 reduces COL10A1 expression, suppresses CAF activity, and reverses EMT and M2 polarization. Pan-cancer analysis suggests that COL10A1+Fib may have similar functional roles across multiple major solid tumors.

Conclusion

Our study identifies a CAF subpopulation, COL10A1+Fib, associated with CRC progression and immune suppression, suggesting it as a potential therapeutic target in CRC and possibly other malignancies.