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

IF 12.8 1区 医学 Q1 ONCOLOGY
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
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引用次数: 0

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.

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。
背景:结直肠癌(CRC)是一种常见的胃肠道肿瘤,治疗反应差,转移风险高。癌症相关成纤维细胞(CAFs)支持肿瘤进展,但其功能异质性尚不清楚。方法:我们整合了来自10164个样本的多组学数据,包括单细胞、批量、空间转录组学和蛋白质组学,以鉴定和表征CAF亚群。通过分子分析、体内模型和药物筛选进行功能验证。结果:我们确定了COL10A1阳性成纤维细胞亚群(COL10A1+Fib)与CRC进展和不良患者预后相关。COL10A1+Fib促进肿瘤细胞增殖、免疫抑制和转移。在机制上,COL10A1+Fib通过COL10A1分泌促进结直肠癌细胞上皮-间质转化(EMT),并通过COL10A1/CD18/JAK1/STAT3信号轴诱导M2巨噬细胞极化。反过来,M2巨噬细胞通过TGF-β/RUNX2途径增强成纤维细胞中COL10A1的表达,形成促肿瘤反馈回路。DNA-PKcs抑制剂NU7441降低COL10A1表达,抑制CAF活性,逆转EMT和M2极化。泛癌分析表明COL10A1+Fib可能在多个主要实体瘤中具有相似的功能作用。结论:我们的研究确定了CAF亚群COL10A1+Fib与CRC进展和免疫抑制相关,表明它可能是CRC和其他恶性肿瘤的潜在治疗靶点。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
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. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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