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Updated: Jun 23, 2025
Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
Published on: November 22, 2019
Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells
Jason S Kirk1, Jie Wang2, Mark Long2
1Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Abstract:
Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here, we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas for interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides a chromatin context, which, when coupled with mouse lineage tracing, demonstrates that castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate AP1 (JUN/FOS), WNT/β-catenin, FOXQ1, NF-κB, and JAK/STAT pathways as major drivers of castration-resistant luminal populations with relevance to human PCa. Our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), can aid in developing combination treatments with ARSI for advanced PCa patients.
Insights
This study created a mouse prostate single-cell atlas to understand castration resistance in prostate cancer (PCa). It identified distinct cell populations and key pathways driving resistance, offering insights for advanced PCa treatments.
Area of Science:
- Oncology
- Genomics
- Cell Biology
Background:
- Prostate cancer (PCa) response to castration and androgen receptor signaling inhibitors (ARSI) is crucial for patient survival.
- Understanding the cellular mechanisms of castration resistance is essential for developing effective treatments.
Purpose of the Study:
- To create a comprehensive mouse single-cell reference atlas of the prostate.
- To interpret mouse prostate biology and castration response using multi-omics data.
- To identify key molecular pathways driving castration resistance in PCa.
Main Methods:
- Utilized a multi-omics approach on 229,794 single cells.
- Developed a mouse single-cell reference atlas.
- Integrated lineage tracing and molecular pathway analysis.
Main Results:
- The reference atlas refined single-cell annotations and provided chromatin context.
- Castration-resistant luminal cells were identified as distinct from urethra-proximal stem/progenitor cells.
- AP1, WNT/β-catenin, FOXQ1, NF-κB, and JAK/STAT pathways were implicated as major drivers of castration-resistant luminal populations.
Conclusions:
- The developed mouse prostate atlas aids in interpreting castration response.
- Identified distinct cell populations and pathways driving castration resistance in PCa.
- Findings are relevant to human PCa and can inform combination therapies with ARSI.
