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

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

doi:10.1016/j.apsb.2023.11.002

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

Acta Pharm Sin B. 2024 Feb;14(2):682-697. doi: 10.1016/j.apsb.2023.11.002. Epub 2023 Nov 4.

Authors

Shuran Fan^{1

2}, Ming Qi^{1

2

3}, Qi Qi⁴, Qun Miao^{1

2}, Lijuan Deng⁵, Jinghua Pan³, Shenghui Qiu³, Jiashuai He³, Maohua Huang^{1

2}, Xiaobo Li^{1

2}, Jie Huang^{1

2}, Jiapeng Lin², Wenyu Lyu², Weiqing Deng², Yingyin He², Xuesong Liu³, Lvfen Gao³, Dongmei Zhang^{1

2}, Wencai Ye^{1

2}, Minfeng Chen^{1

2

6}

Affiliations

¹ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China.
² Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
³ The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
⁴ School of Medicine, Jinan University, Guangzhou 510632, China.
⁵ School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China.
⁶ State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China.

Abstract

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.

Keywords: Colorectal cancer; Epithelial–mesenchymal transition; Extracellular matrix remodeling; FAPα-activated prodrug; Fibroblast activation protein α; Immunosuppressive; Lymphatic metastasis; STAT3.