Dynamic plasticity of prostate cancer intermediate cells during androgen receptor-targeted therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) arises from a lineage switch from androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive states.
• Studying the reversibility of t-SCNC is challenging due to a lack of models for intermediate tumor cell subpopulations.

Purpose of the Study:

• To develop and utilize a novel dual reporter model to investigate acute transcriptional changes in prostate cancer (PC) cells in response to androgen deprivation or AR-targeting agents.
• To identify and characterize intermediate cell subpopulations with dual AR and NE biomarker expression.

Main Methods:

• Development of a dual reporter model to track transcriptional changes in PC cells.
• Analysis of steady-state transcriptional heterogeneity of AR and NE biomarkers.
• Assessment of therapy-induced lineage switching using castration and AR inhibitors.
• Hormone add-back studies to evaluate the reversibility of transcriptional plasticity in PTEN-deficient PC cells and in the presence of secondary genetic drivers like MYCN.

Main Results:

• Identified steady-state transcriptional heterogeneity in AR and NE biomarkers, including intermediate subpopulations co-expressing prostate-specific antigen (PSA) and neuron-specific enolase (NSE) promoter activity.
• Demonstrated that intermediate cells are essential and sufficient for the therapy-induced conversion of PC cells to an NSE-high transcriptional state under castration or AR inhibitor treatment.
• Showed that treatment-induced PSA-NSE transcriptional plasticity is reversible in PTEN-deficient PC cells but not when secondary genetic drivers such as MYCN are present.

Conclusions:

• Intermediate PC cell subpopulations play a critical role in the lineage plasticity driving treatment-emergent neuroendocrine prostate cancer.
• The reversibility of this aggressive neuroendocrine phenotype is dependent on the genetic context, being reversible in PTEN-deficient models but not in the presence of drivers like MYCN.