Follistatin drives AR-independent prostate cancer through BMP signaling inactivation and microenvironmental remodeling
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.
Authors
- Zuyan Fan (ORCID: https://orcid.org/0000-0002-6578-4921)
- Wenjing Su (ORCID: https://orcid.org/0000-0002-1775-9115)
- Liqun Xia (ORCID: https://orcid.org/0000-0001-5040-4992)
- Gonghui Li (ORCID: https://orcid.org/0000-0001-9845-7241)
- Hongliang Gao (ORCID: https://orcid.org/0000-0002-8415-3738)
- Zhifan Ding (ORCID: https://orcid.org/0000-0002-7813-790X)
- Furong Liu (ORCID: https://orcid.org/0000-0002-1142-5966)
- Fang Dong (ORCID: https://orcid.org/0000-0002-9807-5224)
- Xiaoxian Shi
- Wei Xie (ORCID: https://orcid.org/0000-0002-4550-6211)
- Deli Huang (ORCID: https://orcid.org/0000-0002-6989-639X)
- Yizhong Bao (ORCID: https://orcid.org/0000-0002-5245-1212)
- Jing Li (ORCID: https://orcid.org/0000-0002-7973-3930)
- Weijie Zhang (ORCID: https://orcid.org/0000-0002-6462-6067)
- Xu Gao (ORCID: https://orcid.org/0000-0003-1521-9948)
- Biqi Dai
- Min Qu
- Xinhua Feng
- Jun Chen
- Chunjie Lin
- Rushan Chen (ORCID: https://orcid.org/0009-0003-7631-0427)
- Zhiheng Ji
- Yixuan Du
- Tianyu Cao
- Caiwei Tan
Institutions
- Second Military Medical University (CN)
- Sir Run Run Shaw Hospital (CN)
- Zhejiang Cancer Hospital (CN)
- Changhai Hospital (CN)
- Zhejiang Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Institute of Pharmacology (CZ)
- First Affiliated Hospital Zhejiang University (CN)
- Huazhong University of Science and Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1073/pnas.2603564123
- Primary Topic
- TGF-β signaling in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00