THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer

Xing Zhou; Jiashu Han; Anning Zuo; Yuhao Ba; Shutong Liu; Hui Xu; Yuyuan Zhang; Siyuan Weng; Zhaokai Zhou; Long Liu; Peng Luo; Quan Cheng; Chuhan Zhang; Yukang Chen; Dan Shan; Benyu Liu; Shuaixi Yang; Xinwei Han; Jinhai Deng; Zaoqu Liu

doi:10.1186/s12943-024-02180-y

THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer

Mol Cancer. 2024 Dec 28;23(1):282. doi: 10.1186/s12943-024-02180-y.

Authors

Xing Zhou^#^{1

2

3

4}, Jiashu Han^#⁵, Anning Zuo^#¹, Yuhao Ba^#¹, Shutong Liu^#¹, Hui Xu¹, Yuyuan Zhang¹, Siyuan Weng¹, Zhaokai Zhou⁶, Long Liu⁷, Peng Luo⁸, Quan Cheng⁹, Chuhan Zhang¹⁰, Yukang Chen¹, Dan Shan¹¹, Benyu Liu¹², Shuaixi Yang¹³, Xinwei Han^{14

15

16}, Jinhai Deng¹⁷, Zaoqu Liu^{18

19

20

21}

Affiliations

¹ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
² Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China.
³ Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China.
⁴ Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
⁵ Department of General Surgery, Peking Union Medical College Hospital, Beijing, 100020, China.
⁶ Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
⁷ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
⁸ Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁹ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
¹⁰ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
¹¹ Clinical Science Institute, University Hospital Galway, Galway, Ireland.
¹² Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
¹³ Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
¹⁴ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. [email protected].
¹⁵ Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China. [email protected].
¹⁶ Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China. [email protected].
¹⁷ Richard Dimbleby Department of Cancer Research, Comprehensive Cancer Centre, Kings College London, London, UK. [email protected].
¹⁸ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. [email protected].
¹⁹ Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China. [email protected].
²⁰ Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China. [email protected].
²¹ Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. [email protected].

^# Contributed equally.

Abstract

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.

Keywords: COL8A1; Cancer-associated fibroblasts; Colorectal cancer; EMT; Oxaliplatin resistance.

Publication types

Letter

MeSH terms

Animals
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Cell Line, Tumor
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Drug Resistance, Neoplasm* / genetics
Epithelial-Mesenchymal Transition* / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Humans
Integrin beta1 / genetics
Integrin beta1 / metabolism
Mice
Oxaliplatin* / pharmacology
Phosphatidylinositol 3-Kinases* / metabolism
Proto-Oncogene Proteins c-akt* / metabolism
Signal Transduction / drug effects
Thrombospondins* / genetics
Thrombospondins* / metabolism

Substances

Oxaliplatin
Proto-Oncogene Proteins c-akt
thrombospondin 2
Thrombospondins
Phosphatidylinositol 3-Kinases
Integrin beta1

Grants and funding

LHGJ20190388/Henan Province Medical Research Project