THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer
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.
Authors
- Shutong Liu
- Quan Cheng (ORCID: https://orcid.org/0000-0003-2401-5349)
- Yukang Chen
- Jiashu Han (ORCID: https://orcid.org/0009-0007-4000-9893)
- Benyu Liu (ORCID: https://orcid.org/0000-0001-5812-7221)
- Dan Shan (ORCID: https://orcid.org/0009-0008-5153-5917)
- Xinwei Han (ORCID: https://orcid.org/0000-0003-3930-8427)
- Peng Luo (ORCID: https://orcid.org/0000-0002-8215-2045)
- Zhaokai Zhou (ORCID: https://orcid.org/0000-0001-6628-3750)
- Jinhai Deng (ORCID: https://orcid.org/0000-0002-2899-5332)
- Siyuan Weng (ORCID: https://orcid.org/0000-0001-6645-648X)
- Chuhan Zhang (ORCID: https://orcid.org/0009-0003-1505-6787)
- Hui Xu (ORCID: https://orcid.org/0000-0002-1744-4180)
- Long Liu (ORCID: https://orcid.org/0000-0002-3473-2248)
- Yuyuan Zhang (ORCID: https://orcid.org/0000-0002-0972-4537)
- Xing Zhou (ORCID: https://orcid.org/0000-0002-9251-7714)
- Zaoqu Liu (ORCID: https://orcid.org/0000-0002-0452-742X)
- Shuaixi Yang (ORCID: https://orcid.org/0009-0000-7048-8492)
- Anning Zuo (ORCID: https://orcid.org/0009-0006-6779-8282)
- Yuhao Ba
Institutions
- Central South University (CN)
- King's College London (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Zhengzhou University of Light Industry (CN)
- Peking Union Medical College Hospital (CN)
- University Hospital Galway (IE)
- Zhengzhou University (CN)
- London Cancer (GB)
- Henan Energy & Chemical Industry Group (China) (CN)
- Zhujiang Hospital (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Xiangya Hospital Central South University (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Molecular Cancer
- Published
- 2024-12-28
- DOI
- https://doi.org/10.1186/s12943-024-02180-y
- Citations
- 59
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 16.67