THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2024-12-28 DOI:10.1186/s12943-024-02180-y

Xing Zhou, Jiashu Han, Anning Zuo, Yuhao Ba, Shutong Liu, Hui Xu, Yuyuan Zhang, Siyuan Weng, Zhaokai Zhou, Long Liu, Peng Luo, Quan Cheng, Chuhan Zhang, Yukang Chen, Dan Shan, Benyu Liu, Shuaixi Yang, Xinwei Han, Jinhai Deng, Zaoqu Liu

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引用次数: 0

Abstract

Cancer-associated fibroblasts (CAFs) exert multiple tumor-promoting functions and are key contributors to drug resistance. The mechanisms by which specific subsets of CAFs facilitate oxaliplatin resistance in colorectal cancer (CRC) have not been fully explored. This study found that THBS2 is positively associated with CAF activation, epithelial-mesenchymal transition (EMT), and chemoresistance at the pan-cancer level. Together with single-cell RNA sequencing and spatial transcriptomics analyses, we identified THBS2 specifically derived from subsets of CAFs, termed THBS2 + CAFs, which could promote oxaliplatin resistance by interacting with malignant cells via the collagen pathway in CRC. Mechanistically, COL8A1 specifically secreted from THBS2 + CAFs directly interacts with the ITGB1 receptor on resistant malignant cells, activating the PI3K-AKT signaling pathway and promoting EMT, ultimately leading to oxaliplatin resistance in CRC. Moreover, elevated COL8A1 promotes EMT and contributes to CRC oxaliplatin resistance, which can be mitigated by ITGB1 knockdown or AKT inhibitor. Collectively, these results highlight the crucial role of THBS2 + CAFs in promoting oxaliplatin resistance of CRC by activating EMT and provide a rationale for a novel strategy to overcome oxaliplatin resistance in CRC.

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THBS2 +癌相关成纤维细胞通过col8a1介导的PI3K/AKT激活在结直肠癌中促进EMT导致奥沙利铂耐药

癌症相关成纤维细胞（CAFs）发挥多种促肿瘤功能，是耐药的关键因素。特定caf亚群促进结直肠癌（CRC）中奥沙利铂耐药的机制尚未得到充分探讨。本研究发现THBS2在泛癌水平上与CAF激活、上皮-间质转化（epithelial-mesenchymal transition， EMT）和化疗耐药呈正相关。结合单细胞RNA测序和空间转录组学分析，我们确定了THBS2特异性地来源于CAFs亚群，称为THBS2 + CAFs，它可以通过胶原途径在结直肠癌中与恶性细胞相互作用，促进奥沙利铂耐药性。机制上，由THBS2 + CAFs特异性分泌的COL8A1直接与耐药恶性细胞上的ITGB1受体相互作用，激活PI3K-AKT信号通路，促进EMT，最终导致CRC的奥沙利铂耐药。此外，升高的COL8A1促进EMT并促进结直肠癌奥沙利铂耐药，这可以通过ITGB1敲低或AKT抑制剂减轻。总的来说，这些结果突出了THBS2 + CAFs通过激活EMT在促进结直肠癌奥沙利铂耐药中的关键作用，并为克服结直肠癌奥沙利铂耐药的新策略提供了理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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