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Role of ETS factors in specifying prostate luminal cell identity and androgen receptor dependence

ETS 因子在指定前列腺腔细胞身份和雄激素受体依赖性中的作用

基本信息

批准号：
10570242
负责人：
CHARLES L. SAWYERS
金额：
$ 46.22万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570242
关键词：
ATAC-seq Ablation Androgen Receptor Androgens Apoptosis Architecture Automobile Driving Bacteria Basal Cell Binding Sites Biochemical Biological Biological Assay CRISPR library CRISPR screen Cancerous Castration Cell Death Cell Line Cells Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complement Complex Computer Analysis Contracts Coupled DNA DNA Binding Dependence Doxycycline ETS Family Protein ETV4 gene Electrophoretic Mobility Shift Assay Enhancers Enzymes Epigenetic Process Epithelial Cells Epithelium Funding Gene Expression Gene Silencing Genetic Genetic Transcription Genetically Engineered Mouse Genome Goals Growth Factor Human Impairment Investigation Length Ligands Malignant neoplasm of prostate Measures Modeling Mus Mutate Mutation Oncogenic Operative Surgical Procedures Organoids Patients Phenotype Play Proliferating Prostate Prostatic Intraepithelial Neoplasias Proteins Publishing Radical Prostatectomy Reagent Receptor Signaling Relaxation Reproducibility Role Sampling Site Specific qualifier value System Time Tissues Transplantation androgen deprivation therapy biophysical analysis cancer genome cancer initiation deprivation experimental study gain of function in vivo loss of function men novel overexpression paracrine progenitor programs protein protein interaction protein purification receptor receptor binding receptor expression receptor function reconstitution screening single cell analysis single-cell RNA sequencing tool transcription factor transcriptome tumor

项目摘要

ABSTRACT ETS family protein alterations (primarily ERG translocations) are present in >50% of human prostate cancers in Western men. We were the first to develop a robust GEM model of ERG-driven prostate cancer, revealing enhanced luminal differentiation and an expanded androgen receptor (AR) cistrome in tumors, suggesting a novel mechanism for ERG oncogenicity via chromatin programming (Chen, 2013). We and others subsequently established that ERG activates a luminal differentiation program in prostate organoids, human prostate cell lines and, by computational analysis of prostate cancer genomes, in clinical samples (Blee et al., 2018; Kron et al., 2017; Li et al., 2020b). Other ETS gain-of-function alterations e.g. ETV4 translocations (Li et al., 2020a) and ETS loss-of-function alterations e.g. ERF repressor mutations/deletions (Bose et al., 2017) also show this phenotype, as does FOXA1 (also amplified or mutated in prostate cancer) but with a contracted AR cistrome (Adams et al., 2019). Having demonstrated that luminal differentiation is a primary feature of multiple oncogenic ETS proteins (and FOXA1), our major goal during the next funding cycle is to understand how ERG activates this differentiation program and how this program results in an oncogenic phenotype. We will pursue three parallel lines of investigation. First, from our biochemical studies using purified full-length proteins and various DNA templates, we find that that ERG (and other ETS factors) cooperatively enhance AR DNA binding through allosteric effects via direct protein-protein interaction; biologically, this broadens the AR cistrome to include novel AR binding sites (Wasmuth et al., 2020). Aim 1 will expand this analysis to assess the role of FOXA1 on AR/ERG interactions. Second, we have built genetically defined prostate organoid models that recapitulate the luminal differentiation effect of ERG within a precisely defined time course. Using this system, we identified epigenetic changes that silence transcription of the basal epithelial master regulator p63, likely explaining the reduction in basal cells. Aim 2 will use lineage tracing, single cell analysis, and CRISPR screening to further elucidate how ERG expands the number of luminal cells and initiates oncogenic transformation. Third, we showed that another oncogenic ETS protein (ETV4) also drives luminal differentiation and is sufficient, alone, to initiate prostatic intraepithelial neoplasia (PIN). Remarkably, these luminal epithelial cells acquire exquisite dependence on AR for survival (in contrast to normal luminal epithelial cells) and consequently display enhanced sensitivity to androgen deprivation therapy (ADT). Aim 3 will explore mechanisms underlying this shift to cell-intrinsic AR dependence by examining changes in the AR cistrome and transcriptome following luminal-specific AR ablation (by genetic deletion) versus systemic androgen deprivation through surgical castration (impairs AR function in prostate stroma and epithelium). We will complement these experiments with single cell analysis of ETS-positive patient samples before and after ADT.

摘要