Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis

作     者：Shuran Fan Ming Qi Qi Qi Qun Miao Lijuan Deng Jinghua Pan Shenghui Qiu Jiashuai He Maohua Huang Xiaobo Li Jie Huang Jiapeng Lin Wenyu Lyu Weiqing Deng Yingyin He Xuesong Liu Lvfen Gao Dongmei Zhang Wencai Ye Minfeng Chen 

作者机构：State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs ResearchCollege of PharmacyJinan UniversityGuangzhou 510632China School of MedicineJinan UniversityGuangzhou 510632China School of Traditional Chinese MedicineJinan UniversityGuangzhou 510630China The First Affiliated Hospital of Jinan UniversityGuangzhou 510632China State Key Laboratory of Chemical OncogenomicsGuangdong Provincial Key Laboratory of Chemical BiologyTsinghua Shenzhen International Graduate SchoolShenzhen 518055China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第2期

页      面：682-697页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(82273941,81973340,82204427,81803566,82003796,81773758) Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,China) Natural Science Foundation of Guangdong Province(2022A1515011813,2021A1515110242,2020A1515010071,2019A1515010144,2019A1515110543,2019A1515011934,China) Ministry of Science and Technology of China(2018ZX09711001-008-008) National high-level personnel of special support program(Zhang Dongmei),National Key R&D Program of China(2017YFC 1703800) Technology Key Project of Guangdong Province(2020B1111110004,China) Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research,College of Pharmacy(2020B1212060076,China) Special Funds for the Cultivation of Guangdong College Students’Scientifc and Technological Innovation(“Climbing Program”Special Funds)(pdjh2021a0052,China) Science and Technology Projects in Guangzhou(2023A03J0602,202201010173,202102070001,202002030010,China) Young S&T Talent Training Program of Guangdong Provincial Association for S&T,China(SKXRC202216) Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University(JNU1AF-CFTP-2022-a01227,China) China Postdoctoral Science Foundation(2022M 711345,China) 

主　　题：Lymphaticmetastasis Colorectal cancer Fibroblastactivation proteinα FAPα-activated prodrug Epithelial-mesenchymal 

摘      要：Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer(LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha(FAPα) expression in LNM-CRC cells. Gain-or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis(CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.