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
  • 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.
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