Single-Cell Analysis Reveals Pre-Existing Basal-Associated Epithelial States in Metastatic Hormone-Naïve Prostate...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Metastatic hormone-naïve prostate cancer (mHNPC) is aggressive with poor outcomes.
• Intrinsic epithelial cell states at diagnosis are poorly understood.
• Understanding heterogeneity is crucial for targeted therapies.

Purpose of the Study:

• To define epithelial cell states in treatment-naïve mHNPC.
• To investigate tumor heterogeneity and lineage programs.
• To identify potential drivers of aggressive mHNPC biology.

Main Methods:

• Single-cell transcriptomic profiling using Fixed RNA Profiling.
• Analysis of diagnostic prostate biopsy specimens from five mHNPC patients.
• Integrated and case-specific analyses of 17,825 high-quality single cells.

Main Results:

• Epithelial heterogeneity was consistently identified across all mHNPC cases.
• Reproducible basal-associated epithelial populations with reduced AR signaling and stem-like features were observed.
• Epithelial-mesenchymal transition (EMT)-related programs were present but not as distinct clusters; no discrete neuroendocrine cluster was found.

Conclusions:

• Treatment-naïve mHNPC exhibits pre-existing basal-associated epithelial states contributing to intrinsic heterogeneity.
• The presence of AR-low and stem-like cells suggests a role for lineage plasticity in mHNPC aggressiveness.
• These findings highlight potential therapeutic targets for early intervention in mHNPC.