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
{"title":"COL10A1+成纤维细胞促进结直肠癌转移和M2巨噬细胞极化与泛癌相关性。","authors":"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","doi":"10.1186/s13046-025-03510-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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><p><strong>Conclusion: </strong>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>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"243"},"PeriodicalIF":12.8000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360028/pdf/","citationCount":"0","resultStr":"{\"title\":\"COL10A1<sup>+</sup> fibroblasts promote colorectal cancer metastasis and M2 macrophage polarization with pan-cancer relevance.\",\"authors\":\"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\",\"doi\":\"10.1186/s13046-025-03510-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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><p><strong>Conclusion: </strong>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>\",\"PeriodicalId\":50199,\"journal\":{\"name\":\"Journal of Experimental & Clinical Cancer Research\",\"volume\":\"44 1\",\"pages\":\"243\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2025-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360028/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental & Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13046-025-03510-8\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-025-03510-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
COL10A1+ fibroblasts promote colorectal cancer metastasis and M2 macrophage polarization with pan-cancer relevance.
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.
期刊介绍:
The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications.
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