# Investigating lineage plasticity in castration-resistant prostate cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $427,889

## Abstract

Project Summary
 The clinical use of anti-androgens such as abiraterone and enzalutamide has greatly improved prostate
cancer treatment, but patients treated with these drugs still relapse with more aggressive forms of the disease,
collectively termed as castration-resistant prostate cancer (CRPC). These forms of CRPC are characterized by
increased lineage plasticity, often associated with loss of androgen receptor (AR) expression and
neuroendocrine differentiation. Our laboratory focuses on analyses of cell type differentiation in the normal and
transformed prostate epithelium, and has recently used genetically-engineered mouse models to show that
neuroendocrine cells in CRPC arise by transdifferentiation from luminal adenocarcinoma cells. In preliminary
studies for this proposal, we have generated organoid models of CRPC from these mouse prostate tumors, and
have demonstrated by single-cell RNA sequencing that these organoids recapitulate much of the spectrum of
human CRPC, including distinct heterogeneous populations composed of AR-pathway positive prostate cancer,
neuroendocrine prostate cancer, and double-negative prostate cancer. Further analysis of these organoid lines
has revealed a complex genomic landscape of chromatin accessibility, and has identified active histone marks
that are associated with neuroendocrine differentiation. These findings indicate that epigenetic reprogramming
may play a key role in the lineage plasticity of castration-resistant prostate cancer.
 Based on these preliminary data, we hypothesize that molecular analysis of epigenetic reprogramming
in castration-resistant prostate cancer will identify candidate drivers and mechanisms of lineage plasticity. To
investigate this hypothesis, we will pursue three innovative aims that integrate in vivo, ex vivo, molecular, and
computational systems approaches to analyze genetically-engineered mouse models, organoids, grafts, and
human prostate tumor samples. Our specific aims are as follows: (1) Analysis of lineage plasticity in CRPC
organoid and mouse models to examine potential pathways of interconversion between distinct forms of CRPC;
(2) Investigation of epigenetic pathways in CRPC organoid models by examining chromatin accessibility, histone
marks, and DNA methylation patterns to identify epigenetic marks and regulators that drive lineage plasticity;
and (3) Functional analysis of candidate regulators of lineage plasticity in CRPC using computational systems
approaches to identify candidate regulators of plasticity followed by experimental validation using organoid and
graft assays together with analyses of human tumor samples. Overall, these studies will provide essential
insights into the molecular basis of lineage plasticity and treatment resistance in prostate cancer, and will have
significant implications for the development of novel therapies.

## Key facts

- **NIH application ID:** 10033614
- **Project number:** 1R01CA251527-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MICHAEL M. SHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,889
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033614

## Citation

> US National Institutes of Health, RePORTER application 10033614, Investigating lineage plasticity in castration-resistant prostate cancer (1R01CA251527-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10033614. Licensed CC0.

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