Cell-Autonomous AR Dependence in Luminal Prostatic Epithelium Governs Survival and Lineage Plasticity

Area of Science:

• Prostate cancer research
• Cell biology
• Molecular endocrinology

Background:

• Prostate cancer cells depend on androgen receptor (AR) signaling.
• Normal prostate luminal cells are thought to rely on paracrine stromal AR signaling.
• The cell-autonomous role of luminal AR in normal prostate homeostasis is unclear.

Purpose of the Study:

• To investigate the cell-autonomous function of AR in luminal prostate epithelial cells.
• To understand the mechanisms underlying luminal cell fate and regeneration following AR loss.

Main Methods:

• Conditional deletion of the AR gene (Ar) in mouse luminal acinar cells.
• In vivo studies involving cell tracking and lineage analysis.
• Transcriptomic and chromatin profiling (e.g., RNA-seq, ATAC-seq).
• Functional validation using pathway inhibitors (e.g., MAP kinase inhibitors).

Main Results:

• Ar-deleted luminal cells persisted transiently but showed impaired regeneration and progressive loss.
• Basal cells with intact AR differentiated into luminal cells, replacing depleted AR-deleted luminal cells.
• AR loss induced stemness, inflammatory, and epithelial-to-mesenchymal transition (EMT) signatures.
• MAP kinase pathway activation served as a compensatory survival mechanism for AR-deleted luminal cells.

Conclusions:

• Luminal AR intrinsically maintains luminal cell differentiation, plasticity, regeneration, and homeostasis.
• AR loss in luminal cells triggers compensatory pathways and promotes dedifferentiation.
• These findings provide a mechanistic basis for AR dependence in prostate cancer.