TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold‐Sensing TRPM8 Channel

Author:

Li Xiaobo12ORCID,Qi Qi3ORCID,Li Yong24,Miao Qun12,Yin Wenqian12,Pan Jinghua5,Zhao Zhan5,Chen Xiaoying6,Yang Fan6,Zhou Xiaofeng3,Huang Maohua12,Wang Chenran12,Deng Lijuan7,Huang Dandan8,Qi Ming12,Fan Shuran12,Zhang Yiran5,Qiu Shenghui5,Deng Weiqing2,Liu Tongzheng2,Chen Minfeng12ORCID,Ye Wencai12ORCID,Zhang Dongmei12ORCID

Affiliation:

1. State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University Guangzhou 510632 China

2. College of Pharmacy Jinan University Guangzhou 510632 China

3. MOE Key Laboratory of Tumor Molecular Biology Clinical Translational Center for Targeted Drug Department of Pharmacology School of Medicine Jinan University Guangzhou 510632 China

4. School of Pharmacy North Sichuan Medical College Nanchong 637100 China

5. Department of General Surgery The First Affiliated Hospital of Jinan University Guangzhou 510632 China

6. Department of Biophysics Kidney Disease Center of First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310058 China

7. Formula‐Pattern Research Center School of Traditional Chinese Medicine Jinan University Guangzhou 510632 China

8. The Sixth Affiliated Hospital of Sun Yet‐Sen University Guangzhou 510655 China

Abstract

AbstractHematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium‐based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel‐associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease‐free survival in CRC patients. Gain‐ and loss‐of‐function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial‐mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte‐conditional Tcaf2‐knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro‐metastatic effects of TPCs from the perspective of cold‐sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

National Key Research and Development Program of China

China Postdoctoral Science Foundation

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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