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Updated: Sep 26, 2026

Isolation, Culture, and Characterization of Prostate Cancer-Associated Fibroblasts
Published on: August 1, 2025
Follistatin drives AR-independent prostate cancer through BMP signaling inactivation and microenvironmental
Xiaoxian Shi1,2, Zuyan Fan2, Min Qu3
1Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China.
Abstract:
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.
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