Document text
Principal Investigator: MICHAEL M. SHEN
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $406,495
Funding agency: National Cancer Institute
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.
Terms: <3-D><3-Dimensional><3D><Adenocarcinoma><Adenocarcinoma Cell><Adopted><Affect><Androgen Antagonists><Androgen Receptor><Anti-Androgen><Anti-Androgen Agents><Anti-androgen Therapy><Anti-androgen Treatment><Assay><BS-seq><Bioassay><Biochemical><Biologic Models><Biological Assay><Biological Models><Bisulfite-based sequencing><CRISPR><CRISPR/Cas system><Cell Body><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Characteristics><Chromatin><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Complex><Computer Analysis><DNA Methylation><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA-Methyltransferases><DNMT3a><Data><Development><Disease><Disorder><Dnmt><Drugs><ENX-1><EZH1><EZH2><EZH2 gene><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><GEM model><GEMM model><Genetically Engineered Mouse><Genitourinary><Genitourinary system><Genomics><Histones><Human><Investigation><KMT6><KMT6A><Laboratories><Malignant Adenoma><Malignant Glandular Cell><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Metastatic Prostate Cancer><Mice><Mice Mammals><Model System><Modeling><Modern Man><Modification><Modification Methylases><Molecular><Molecular Analysis><Murine><Mus><Neuroendocrine><Neuroendocrine Cell><Neuroendocrine Neoplasm><Neuroendocrine Prostate Cancer><Neuroendocrine System><Neuroendocrine Tumors><Neurosecretory Systems><Organoids><Pathology><Pathway interactions><Patients><Pattern><Pharmaceutical Preparations><Phenotype><Play><Polycomb><Population><Population Heterogeneity><Property><Prostate><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Carcinoma Metastatic><Prostate Gland><Prostate Neoplasms><Prostate Tumor><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Prostatic Neoplasia><Prostatic Neoplasms><Relapse><Resistance><Sampling><Site-Specific DNA-methyltransferase><Specific qualifier value><Specified><System><Systems Biology><Transitional Cell><Urogenital><Urogenital System><Validation><Xtandi><abiraterone><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen inhibitor><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><bisulfite sequencing><bisulfite-seq><candidate identification><candidate validation><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cell type><chromatin immunoprecipitation-sequencing><computational analyses><computational analysis><computer analyses><developmental><diverse populations><drug candidate><drug/agent><effective therapy><effective treatment><entire genome><enzalutamide><epigenetic regulation><epigenetically><full genome><gain of function><genetically engineered mouse model><genetically engineered murine model><hDNA methyltransferase 3a><heterogeneous population><hormone refractory prostate cancer><improved><in vivo><innovate><innovation><innovative><insight><interest><methylation pattern><mouse model><murine model><neuroendocrine differentiation><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pathway><pharmacologic><population diversity><programs><prostate cancer resistant to androgen><prostate cancer treatment><receptor expression><recruit><resistance to therapy><resistant><resistant to therapy><scATAC sequencing><scATAC-seq><scRNA-seq><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><therapeutic resistance><therapeutic target><therapy resistant><three dimensional><transdifferentiation><translational impact><treatment resistance><tumor><validations><whole genome>