Investigating lineage plasticity in castration-resistant prostate cancer

研究去势抵抗性前列腺癌的谱系可塑性

基本信息

批准号：
10033614
负责人：
MICHAEL M. SHEN
金额：
$ 42.79万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10033614
关键词：
3-Dimensional Adenocarcinoma Adenocarcinoma Cell Adopted Affect Androgen Antagonists Androgen Receptor Antiandrogen Therapy Biochemical Biological Assay Biological Models Cells ChIP-seq Characteristics Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Analysis DNA Methylation DNA Modification Methylases Data Development Disease EZH2 gene Epigenetic Process Epithelial Epithelium Genetically Engineered Mouse Genitourinary system Genomics Histones Human Investigation Laboratories Lead Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Modeling Modification Molecular Molecular Analysis Molecular Computations Mus Neuroendocrine Cell Neuroendocrine Tumors Neurosecretory Systems Organoids Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Play Polycomb Population Population Heterogeneity Property Prostate Prostate Cancer therapy Prostatic Neoplasms Relapse Resistance Sampling System Systems Biology Transitional Cell Validation XCL1 gene abiraterone base bisulfite sequencing candidate validation castration resistant prostate cancer cell type drug candidate effective therapy epigenetic regulation gain of function improved in vivo innovation insight interest methylation pattern mouse model neuroendocrine differentiation new therapeutic target novel novel therapeutics programs receptor expression recruit single-cell RNA sequencing therapeutic target therapy resistant transdifferentiation translational impact tumor whole genome

项目摘要

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.

项目概要临床使用阿比特龙、恩杂鲁胺等抗雄激素对前列腺有很大改善癌症治疗，但接受这些药物治疗的患者仍然会复发，并出现更具侵袭性的疾病，统称为去势抵抗性前列腺癌（CRPC）。这些形式的 CRPC 的特点是谱系可塑性增加，通常与雄激素受体（AR）表达的丧失有关神经内分泌分化。我们的实验室专注于正常和正常细胞类型分化的分析转化前列腺上皮，最近使用基因工程小鼠模型表明 CRPC 中的神经内分泌细胞是由管腔腺癌细胞转分化产生的。在初步为了这项提案的研究，我们从这些小鼠前列腺肿瘤中生成了 CRPC 类器官模型，并且通过单细胞 RNA 测序证明，这些类器官概括了大部分人类 CRPC，包括由 AR 通路阳性前列腺癌组成的不同异质群体，神经内分泌前列腺癌和双阴性前列腺癌。对这些类器官系的进一步分析揭示了染色质可及性的复杂基因组景观，并鉴定了活性组蛋白标记与神经内分泌分化有关。这些发现表明表观遗传重编程可能在去势抵抗性前列腺癌的谱系可塑性中发挥关键作用。基于这些初步数据，我们假设表观遗传重编程的分子分析在去势抵抗性前列腺癌中，将确定谱系可塑性的候选驱动因素和机制。到研究这一假设，我们将追求三个创新目标，将体内、离体、分子和计算系统方法来分析基因工程小鼠模型、类器官、移植物和人类前列腺肿瘤样本。我们的具体目标如下：（1）CRPC谱系可塑性分析类器官和小鼠模型，用于检查不同形式的 CRPC 之间潜在的相互转化途径； (2) 通过检查染色质可及性、组蛋白来研究 CRPC 类器官模型中的表观遗传通路标记和 DNA 甲基化模式，以识别驱动谱系可塑性的表观遗传标记和调节因子； (3) 使用计算系统对 CRPC 谱系可塑性候选调节因子进行功能分析确定可塑性候选调节因子的方法，然后使用类器官进行实验验证移植物测定以及人类肿瘤样本的分析。总体而言，这些研究将提供必要的深入了解前列腺癌谱系可塑性和治疗耐药性的分子基础，并将对新疗法的开发具有重要意义。