Project 3: Analysis of intrinsic and extrinsic factors that promote prostate neuroendocrine differentiation

项目3：促进前列腺神经内分泌分化的内在和外在因素分析

基本信息

批准号：
10612357
负责人：
MICHAEL M. SHEN
金额：
$ 42.67万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612357
关键词：
Abate Address Androgen Antagonists Androgen Receptor Androgens Bioinformatics Biological Assay Candidate Disease Gene Cells Clinical Collaborations Comparative Study Computer Analysis Data Development Disease Environment Epithelium FGFR1 gene Generations Genetic Complementation Test Genetically Engineered Mouse Heterogeneity Human Intrinsic factor Investigation Ligands Malignant Neoplasms Malignant neoplasm of prostate Mesenchyme Modeling Molecular Molecular Analysis Molecular Target Mus NCAM1 gene Neuroendocrine Cell Neuroendocrine Prostate Cancer Neurosecretory Systems Organogenesis Organoids Pathway interactions Pattern Primary Neoplasm Prostate Prostatic Neoplasms Receptor Inhibition Role Sampling Signal Transduction Specific qualifier value System Tissue Recombination Tissue Sample Tissues Validation Visualization WNT Signaling Pathway Work candidate identification castration resistant prostate cancer cell type comparative data management deprivation effective therapy human tissue in vivo innovation interest mouse model multiplexed imaging neoplastic cell neuroendocrine differentiation neuroendocrine phenotype novel prepuberty programs prostate cancer cell receptor response single-cell RNA sequencing synergism therapeutic target therapy resistant transcription factor transdifferentiation translational impact tumor tumor microenvironment tumorigenic

项目摘要

Project Summary/Abstract The clinical use of potent anti-androgens has promoted the emergence of novel forms of castration- resistant prostate cancer (CRPC), including neuroendocrine prostate cancer (NEPC), which is highly aggressive and lethal. To date, relatively little is known about the regulatory programs for specification of rare neuroendocrine cells in the normal prostate, or how they might be recapitulated or altered during neuroendocrine differentiation in prostate cancer. Therefore, we will pursue a comparative analysis of neuroendocrine specification in the normal and transformed prostate to elucidate similarities and differences in their regulatory programs. In preliminary studies of prostate organogenesis, our findings suggest that prostate neuroendocrine cells are generated at pre-pubertal stages of organogenesis, when androgen levels are low, and that the transcription factor Ascl1 is essential for formation of prostate neuroendocrine cells. To complement these analyses, we have also performed studies of neuroendocrine differentiation in prostate tumors through single- cell RNA-sequencing of mouse CRPC tumors and organoid models to identify candidate non-cell autonomous interactions that may regulate neuroendocrine differentiation, as well as computational analyses to identify novel candidate master regulators of neuroendocrine differentiation in tumors. Importantly, we have obtained evidence for a non-cell autonomous role for extrinsic signals from the microenvironment in promoting neuroendocrine differentiation of prostate tumor cells. Based on our preliminary data, we hypothesize that neuroendocrine differentiation in both normal and tumor contexts is governed by extrinsic signals from the environment in response to low AR activity in order to regulate intrinsic pathways of neuroendocrine specification. To investigate this hypothesis, we will pursue an innovative combination of in vivo, ex vivo, molecular, and computational analyses that are organized in three synergistic specific aims: (1) Investigation of Ascl1 in prostate development and cancer to pursue comparative analyses of its role in normal and tumor contexts; (2) Investigation of intrinsic regulators of neuroendocrine differentiation in prostate cancer using computational systems approaches to identify candidate master regulators followed by their functional validation; and (3) Analysis of stromal signals that promote neuroendocrine differentiation in response to androgen deprivation to evaluate the role of candidate signaling factors from the microenvironment in modulating neuroendocrine differentiation in response to AR in organogenesis and prostate cancer. These studies will have strong translational impact through the identification of molecular targets that are specific for neuroendocrine prostate cancer. Furthermore, this project will be highly integrated with the other components of this program project through collaborative interactions with the Sawyers lab in analyzing microenvironmental signals, with the Abate-Shen lab in studies of mouse models, with Core A in analysis of human tissue samples, and Core B for statistical support and data management,

项目概要/摘要强效抗雄激素的临床使用促进了新形式去势的出现耐药性前列腺癌 (CRPC)，包括高度侵袭性的神经内分泌前列腺癌 (NEPC) 和致命的。迄今为止，人们对稀有物质规范的监管计划知之甚少。正常前列腺中的神经内分泌细胞，或者它们在神经内分泌过程中如何重演或改变前列腺癌的分化。因此，我们将对神经内分泌进行比较分析。正常和转化前列腺的规范，以阐明其调节方面的相似性和差异程序。在前列腺器官发生的初步研究中，我们的研究结果表明前列腺神经内分泌细胞在器官发生的青春期前阶段产生，此时雄激素水平较低，并且转录因子 Ascl1 对于前列腺神经内分泌细胞的形成至关重要。为了补充这些分析中，我们还通过单细胞研究对前列腺肿瘤的神经内分泌分化进行了研究。对小鼠 CRPC 肿瘤和类器官模型进行细胞 RNA 测序，以确定候选非细胞自主性可能调节神经内分泌分化的相互作用，以及识别新的计算分析肿瘤神经内分泌分化的候选主调节因子。重要的是我们已经拿到了证据来自微环境的外在信号在促进神经内分泌方面的非细胞自主作用前列腺肿瘤细胞的分化。根据我们的初步数据，我们假设正常和中枢神经内分泌分化肿瘤环境受到来自环境的外在信号的控制，以响应低 AR 活性，以便调节神经内分泌规范的内在途径。为了研究这个假设，我们将追求体内、离体、分子和计算分析的创新组合，分为三个部分协同具体目标：（1）研究Ascl1在前列腺发育和癌症中的作用，以进行比较分析其在正常和肿瘤环境中的作用； (2)神经内分泌内在调节因子的研究使用计算系统方法识别候选主控前列腺癌的分化监管机构随后进行功能验证； (3)促进神经内分泌的基质信号分析响应雄激素剥夺的分化，以评估候选信号因子的作用微环境在器官发生和前列腺中调节神经内分泌分化以响应 AR 癌症。这些研究将通过识别分子靶点产生强大的转化影响是针对神经内分泌前列腺癌的特异性药物。此外，该项目将与其他项目高度集成该项目的组成部分通过与 Sawyers 实验室的协作互动进行分析微环境信号，与 Abate-Shen 实验室一起研究小鼠模型，与 Core A 一起分析人体组织样本，以及用于统计支持和数据管理的核心 B，