THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis
Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.
Authors
- Shutong Liu (ORCID: https://orcid.org/0000-0003-0976-4966)
- Xinghuan Wang (ORCID: https://orcid.org/0000-0003-3497-0024)
- Quan Cheng (ORCID: https://orcid.org/0000-0003-2401-5349)
- Benyu Liu (ORCID: https://orcid.org/0000-0001-5812-7221)
- Dan Shan (ORCID: https://orcid.org/0009-0008-5153-5917)
- Peng Luo (ORCID: https://orcid.org/0000-0002-8215-2045)
- Jinhai Deng (ORCID: https://orcid.org/0000-0002-2899-5332)
- Siyuan Weng (ORCID: https://orcid.org/0000-0001-6645-648X)
- Xinwei Han (ORCID: https://orcid.org/0000-0003-4407-4864)
- Ruizhi Wang (ORCID: https://orcid.org/0000-0003-2535-9944)
- Yuyuan Zhang (ORCID: https://orcid.org/0000-0002-0972-4537)
- Hui Xu (ORCID: https://orcid.org/0009-0007-9551-0634)
- Xing Zhou (ORCID: https://orcid.org/0000-0002-9251-7714)
- Xin‐Hua Hu (ORCID: https://orcid.org/0000-0001-5038-7651)
- Shuaixi Yang (ORCID: https://orcid.org/0009-0000-7048-8492)
- Zaoqu Liu
- Anning Zuo (ORCID: https://orcid.org/0009-0006-6779-8282)
- Yuhao Ba
- Yanan Zhao
Institutions
- Central South University (CN)
- King's College London (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wuhan University (CN)
- Zhengzhou University (CN)
- London Cancer (GB)
- Zhongnan Hospital of Wuhan University (CN)
- Zhujiang Hospital (CN)
- First Affiliated Hospital of Henan University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Xiangya Hospital Central South University (CN)
- Southern Medical University (CN)
- Lancaster University (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115555
- Citations
- 17
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 13.56
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Henan Provincial Science and Technology Research Project