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

Zaoqu Liu; Yuhao Ba; Dan Shan; Xing Zhou; Anning Zuo; Yuyuan Zhang; Hui Xu; Shutong Liu; Benyu Liu; Yanan Zhao; Siyuan Weng; Ruizhi Wang; Jinhai Deng; Peng Luo; Quan Cheng; Xin Hu; Shuaixi Yang; Fubing Wang; Xinwei Han

doi:10.1016/j.celrep.2025.115555

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. Epub 2025 Apr 12.

Authors

Zaoqu Liu¹, Yuhao Ba², Dan Shan³, Xing Zhou⁴, Anning Zuo², Yuyuan Zhang², Hui Xu², Shutong Liu², Benyu Liu⁵, Yanan Zhao⁶, Siyuan Weng², Ruizhi Wang², Jinhai Deng⁷, Peng Luo⁸, Quan Cheng⁹, Xin Hu¹⁰, Shuaixi Yang¹¹, Fubing Wang¹², Xinwei Han¹³

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.

MeSH terms

Animals
CD47 Antigen* / metabolism
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Cell Line, Tumor
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Cyclic AMP Response Element-Binding Protein / metabolism
Disease Progression
Humans
MAP Kinase Signaling System*
Male
Mice
Mice, Knockout
Prognosis
Thrombospondins* / genetics
Thrombospondins* / metabolism
Tumor Microenvironment

Substances

thrombospondin 2
Thrombospondins
CD47 Antigen
CD47 protein, human
Cyclic AMP Response Element-Binding Protein