2. Academic Validation
  3. Enzalutamide-Resistant STEAP4+ MyoCAF Secrete Phosphatidylcholine to Foster Progression by Activating Stemness in Hormone-Sensitive Prostate Cancer

Enzalutamide-Resistant STEAP4+ MyoCAF Secrete Phosphatidylcholine to Foster Progression by Activating Stemness in Hormone-Sensitive Prostate Cancer

  • Adv Sci (Weinh). 2025 Sep 8:e10602. doi: 10.1002/advs.202510602.
Wenhao Wang 1,  Jing Zhao 1,  Tiewen Li 1,  Guangjian Fan 1 2,  Jianong Zhang 1 2,  Chenghao Zheng 1,  Zhiwen Xie 1,  Yu Zhang 1,  Chengling Feng 1,  Tianyu Cao 1,  Jianyin Li 3,  Guomin Ju 4,  Di Cui 1,  Shujie Xia 1,  Bangmin Han 1
Affiliations

Affiliations

  • 1 Department of Urology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • 2 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 3 Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
  • 4 Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
PMID: 40917018 DOI: 10.1002/advs.202510602
Abstract

Despite the expanding clinical application of second-generation anti-androgens like enzalutamide (ENZ) in hormone-sensitive prostate Cancer (HSPC), therapeutic resistance culminating in castration-resistant prostate Cancer (CRPC) persists as an unresolved clinical crisis. Through comprehensive single-cell transcriptomic profiling of ENZ-naïve and ENZ-treated tumors, an expansion of ENZ-resistant myofibroblastic cancer-associated fibroblast (designated STEAP4+ myoCAF) is identified that correlates with adverse clinical outcomes. Strikingly, STEAP4+ myoCAF demonstrated intrinsic ENZ resistance through a mechanistically novel pathway involving transcription factor binding to IGHM enhancer 3 (TFE3)-mediated Autophagy activation. Integrated lipidomic and functional analyses revealed that TFE3 activation drives phosphatidylcholine overproduction via direct upregulation of phosphate cytidylyltransferase 1A (PCYT1A), establishing a tumor-promoting feedforward loop. The resultant phospholipid-rich microenvironment activates an HSP90/HIF1A signaling axis in malignant epithelial cells, fueling Cancer stemness and therapeutic escape. These findings position the STEAP4+ myoCAF-TFE3/tumor-HIF1A axis as a master regulator of anti-androgen resistance, offering clinically actionable targets to extend treatment efficacy in advanced prostate Cancer.

Keywords

autophagy; cancer‐associated fibroblasts; enzalutamide; phosphatidylcholine; prostate cancer; stemness.

Figures
Products