THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis

  • Cell Rep. 2025 Apr 22;44(4):115555. doi: 10.1016/j.celrep.2025.115555.
Zaoqu Liu  1 ,  Yuhao Ba  2 ,  Dan Shan  3 ,  Xing Zhou  4 ,  Anning Zuo  2 ,  Yuyuan Zhang  2 ,  Hui Xu  2 ,  Shutong Liu  2 ,  Benyu Liu  5 ,  Yanan Zhao  6 ,  Siyuan Weng  2 ,  Ruizhi Wang  2 ,  Jinhai Deng  7 ,  Peng Luo  8 ,  Quan Cheng  9 ,  Xin Hu  10 ,  Shuaixi Yang  11 ,  Fubing Wang  12 ,  Xinwei Han  13
Affiliations
  • 1. Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: [email protected].
  • 2. Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
  • 3. Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YT, UK.
  • 4. Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
  • 5. Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 6. Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China.
  • 7. Richard Dimbleby Department of Cancer Research, Comprehensive Cancer Centre, Kings College London, London, UK.
  • 8. Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 9. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 10. Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China; Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
  • 11. Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China. Electronic address: [email protected].
  • 12. Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China; Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China; Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: [email protected].
  • 13. Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China. Electronic address: [email protected].
PMID: 40222008 DOI: 10.1016/j.celrep.2025.115555
Abstract

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.

Keywords
CAFs; CP: Cancer; THBS2; colorectal cancer; mCAF; prognosis.
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