Xuanming Chen, Jue Li, Cheng Shen, Chunxiu Xiao, Siqi Li, Qiyi Feng, Shuwen Xiao, Jingyao Chen, Manyu Zhao, Siyang Song, Jialong Li, Yuhang Kong, Panwen Tian, Guowei Che, Weimin Li, Kai Xiao
Cancer-associated fibroblast (CAF)-derived extracellular vesicles (EVs) mediate lung adenocarcinoma (LUAD) progression, but the role of their protein cargo remains poorly defined. Through quantitative proteomic profiling of EVs from patient-derived CAFs, we identify the V-ATPase subunit ATP6V1C1 as a protein highly enriched in pro-migratory CAF-EVs that critically mediates LUAD metastasis. Mechanistically, EV-delivered ATP6V1C1 suppresses insulin-like growth factor binding protein 3 (IGFBP3) expression by downregulating the transcriptional regulator ID1. This suppression of IGFBP3 induces epithelial-mesenchymal transition in LUAD cells and amplifies the oncogenic IGF1/IGF1R/Akt/ERK signaling cascade initiated by CAF-secreted IGF1. This dual action establishes a feedforward loop that exacerbates metastatic progression. Our findings identify ATP6V1C1 as a dual regulator of LUAD metastasis and suggest a potential stroma-targeted therapeutic approach.