THBS2 + cancer-associated Fibroblasts Promote EMT Leading to Oxaliplatin Resistance Via COL8A1-mediated PI3K/AKT Activation in Colorectal Cancer

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2024 Dec 28

PMID 39732719

Authors

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

Affiliations

Soon will be listed here.

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.

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