Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1

Area of Science:

• Oncology
• Cancer Biology
• Molecular Urology

Background:

• Androgen receptor (AR)-targeted therapies are often overcome by prostate adenocarcinoma, leading to aggressive AR-independent neuroendocrine prostate cancer (NEPC).
• NEPC progression is hypothesized to involve lineage plasticity, where AR-dependent tumors transform into an AR-independent NE state.
• Loss of RB1 and TP53, along with ASCL1 and NEUROD1 expression, are implicated in NEPC development.

Purpose of the Study:

• To establish an in vivo model for studying prostate adenocarcinoma progression to NEPC.
• To investigate the role of the lineage transcription factor ASCL1 in NEPC differentiation.

Main Methods:

• Genetically engineered mouse models (RPM) with Cre-induced loss of Rb1 and Trp53 and Myc overexpression were used to generate prostate organoids and allograft tumors.
• Tumor heterogeneity, including adenocarcinoma, squamous, and NE features, was analyzed.
• ASCL1 was genetically deleted to assess its impact on NE identity and tumor progression.

Main Results:

• The RPM model generated heterogeneous tumors displaying adenocarcinoma, squamous, and NE phenotypes.
• ASCL1 was predominantly expressed in NE regions and its loss reduced NE identity while increasing basal-like identity.
• Genetic deletion of Ascl1 did not affect tumor incidence, growth, or metastasis but significantly impacted NE differentiation.

Conclusions:

• The developed in vivo model effectively recapitulates prostate adenocarcinoma progression to NEPC.
• ASCL1 is essential for driving neuroendocrine differentiation in prostate cancer, highlighting its potential as a therapeutic target.
• Understanding lineage plasticity and transcription factor dependencies is critical for treating aggressive NEPC.