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