Proceedings of the National Academy of Sciences of the United States of America · 2026
Follistatin drives AR-independent prostate cancer through BMP signaling inactivation and microenvironmental remodeling.
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Shi Xiaoxian, Fan Zuyan, Qu Min, Lin Chunjie, Ji Zhiheng, Tan Caiwei, Dai Biqi, Chen Rushan, Du Yixuan, Bao Yizhong, Ding Zhifan, Xia Liqun, Liu Furong, Gao Hongliang, Cao Tianyu, Xie Wei, Fang Dong, Zhang Weijie, Huang Deli, Chen Jun, Gao Xu, Feng Xinhua, Li Gonghui, Li Jing, Su Wenjing
Аннотация
Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in advanced prostate cancer. Here we identify follistatin (FST), TGFβ superfamily antagonist, as a key driver of AR-independence and treatment resistance. During anti-AR therapy, cancer cells progressively lose the positive feedback loop between AR and BMP signaling, leading to FST upregulation that further suppresses this circuit. FST antagonizes BMP11-dependent AR maintenance and upregulates the lineage plasticity regulator SOX9, conferring resistance to enzalutamide while promoting stem-like properties and metastatic capabilities. FST also remodels the tumor microenvironment by driving osteoclastogenesis and compromising T cell effector function. Clinically, FST inversely correlates with PSA levels and associates with poor outcomes in enzalutamide-treated patients. We developed FST-Trap, which effectively neutralizes FST, resensitizes resistant tumors to AR-targeted therapy, and enhances immunotherapy efficacy. This establishes FST as both a biomarker and therapeutic target for AR-independent prostate cancer.