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Updated: Nov 2, 2025
Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
Published on: November 22, 2019
Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer
Nicholas J Brady1, Alyssa M Bagadion1, Richa Singh1
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Abstract:
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.
Insights
Researchers identified key genetic changes driving the progression of prostate cancer to a treatment-resistant, neuroendocrine form. This study reveals how Rb1 loss and N-Myc overexpression lead to aggressive, AR-negative neuroendocrine prostate cancer (NEPC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Advanced prostate cancer often develops resistance to androgen receptor (AR)-directed therapies.
- A subset of resistant tumors lose AR expression, gain neuroendocrine features (NEPC), and exhibit poor differentiation and high metastatic potential.
- The molecular mechanisms driving the transition from AR-positive adenocarcinoma to AR-negative NEPC remain poorly understood.
Purpose of the Study:
- To characterize the cellular heterogeneity and molecular evolution during the progression from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC).
- To investigate the synergistic effects of Rb1 loss and MYCN (N-Myc) overexpression in driving NEPC development.
Main Methods:
- Utilized a novel genetically engineered mouse model for prostate cancer.
- Employed single-cell-based approaches to analyze transcriptomic and chromatin accessibility changes.
- Performed global DNA methylation analysis and N-Myc cistrome profiling.
Main Results:
- Rb1 loss combined with MYCN overexpression induced AR-negative, poorly differentiated tumors with high metastatic potential.
- Single-cell analysis revealed temporal transcriptome and chromatin accessibility shifts, identifying distinct cell populations marked by Ascl1 and Pou2f3 expression during NEPC transition.
- Rb1 loss led to global DNA methylation changes and redirected N-Myc binding.
Conclusions:
- The study elucidates the molecular pathways and cellular dynamics involved in the progression to NEPC.
- Findings highlight the critical roles of Rb1 and N-Myc in driving the aggressive phenotype of NEPC.
- This research provides crucial insights into the evolution of prostate cancer towards a neuroendocrine subtype.
