2. Academic Validation
  3. THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis

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

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: liuzaoqu@163.com.
  • 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: sxyang@zzu.edu.cn.
  • 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: wfb20042002@sina.com.
  • 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: fcchanxw@zzu.edu.cn.
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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