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Updated: Jan 18, 2026

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients

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Enzalutamide-Resistant STEAP4+ MyoCAF Secrete Phosphatidylcholine to Foster Progression by Activating Stemness in

Wenhao Wang1, Jing Zhao1, Tiewen Li1

  • 1Department of Urology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 8, 2025
PubMed

Insights

Enzalutamide resistance in prostate cancer involves STEAP4+ myofibroblastic cancer-associated fibroblasts activating autophagy and lipid production. This creates a tumor-promoting microenvironment, driving therapeutic escape and resistance to anti-androgen treatments.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Therapeutic resistance to enzalutamide (ENZ) remains a significant challenge in treating advanced prostate cancer, leading to castration-resistant prostate cancer (CRPC).
  • Understanding the mechanisms driving ENZ resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To identify novel cellular mechanisms and pathways contributing to enzalutamide resistance in prostate cancer.
  • To elucidate the role of cancer-associated fibroblasts in mediating therapeutic resistance.

Main Methods:

  • Comprehensive single-cell transcriptomic profiling of hormone-sensitive prostate cancer (HSPC) and ENZ-treated tumors.
  • Integrated lipidomic and functional analyses to investigate molecular pathways.
  • Analysis of transcription factor binding and signaling axis activation.

Main Results:

  • Identified an expansion of STEAP4+ myofibroblastic cancer-associated fibroblasts (myoCAFs) associated with poor clinical outcomes and ENZ resistance.
  • Discovered a novel pathway where TFE3 transcription factor activation in STEAP4+ myoCAFs drives autophagy and phosphatidylcholine overproduction via PCYT1A.
  • Demonstrated that this phospholipid-rich microenvironment activates HSP90/HIF1A signaling in cancer cells, promoting stemness and therapeutic escape.

Conclusions:

  • The STEAP4+ myoCAF-TFE3/tumor-HIF1A axis is a key regulator of anti-androgen resistance in prostate cancer.
  • Targeting this axis presents a promising therapeutic strategy to overcome enzalutamide resistance and improve treatment efficacy in advanced prostate cancer.
Keywords:
autophagycancer‐associated fibroblastsenzalutamidephosphatidylcholineprostate cancerstemness

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