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Updated: Jun 14, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
ASCL1 Drives the Development of Neuroendocrine Prostate Cancer
Caden N McQuillen1, Nicholas J Brady2
1Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Therapeutic resistance to androgen receptor (AR)-targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss. See related article by Rodarte et al., p. 3522.
Insights
Androgen receptor (AR)-targeted therapy resistance in prostate cancer is a major issue. ASCL1 is essential for neuroendocrine prostate cancer (NEPC) development, and its loss redirects tumor cells to a basal-like phenotype.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Therapeutic resistance to androgen receptor (AR)-targeting agents is a significant clinical challenge in prostate cancer treatment.
- Prostate tumors can escape AR-targeted therapies through lineage plasticity and progression to neuroendocrine prostate cancer (NEPC).
- While genetic alterations can predispose tumors to NEPC, essential drivers for this progression remain largely unidentified.
Purpose of the Study:
- To identify essential regulators driving the progression to neuroendocrine prostate cancer (NEPC).
- To investigate the role of ASCL1 in NEPC development and lineage plasticity.
- To establish a new model for studying NEPC and its phenotypic changes.
Main Methods:
- Utilized genetically engineered mouse models to study prostate cancer progression.
- Analyzed the impact of ASCL1 expression and loss on tumor cell phenotypes and lineage trajectories.
- Investigated the potential for ASCL1+ NEPC cells to transition to a NEUROD1+ state.
Main Results:
- ASCL1 was found to be dispensable for initial tumor formation and growth.
- Loss of ASCL1 significantly abrogated the development of NEPC, redirecting lineage towards a basal-like phenotype.
- Demonstrated that ASCL1+ NEPC cells can also exhibit a NEUROD1+ phenotype, highlighting plasticity.
Conclusions:
- ASCL1 is identified as an essential regulator for the development of neuroendocrine prostate cancer (NEPC).
- ASCL1 loss promotes a shift in prostate cancer lineage plasticity, favoring a basal-like phenotype over NEPC.
- This research provides a novel model for NEPC studies and elucidates the phenotypic consequences of ASCL1 modulation in prostate cancer.
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