Mechanisms of Prostate Cancer Metastasis

前列腺癌转移的机制

• 批准号: 10706309
• 负责人: Michael R Freeman
• 金额: $ 42.69万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706309
• 关键词: 3-Dimensional; Androgen Receptor; Aneuploidy; Bioinformatics; Biological Assay; Biological Models; Bone Marrow; Breast Cancer Cell; Bulla; Castration; Cell Separation; Cessation of life; Chromosomal Instability; Clonal Expansion; Cytoplasm; Diagnostic; Disease; Down-Regulation; Epithelium; Exhibits; Expression Profiling; Family; Funding; Genes; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomic Instability; Goals; Growth; Histologic; Histology; Human; Hypoxia; Longterm Follow-up; Malignant neoplasm of prostate; Membrane Proteins; Mesenchymal; Metastatic Prostate Cancer; Methods; Molecular; Mus; Needle biopsy procedure; Neoplasm Circulating Cells; Neoplasm Metastasis; Neurosecretory Systems; Newly Diagnosed; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Patients; Phenotype; Ploidies; Population; Primary Neoplasm; Process; Property; Prostate; Prostatic Neoplasms; Receptor Signaling; Reporting; Resistance; Role; Shapes; Signal Transduction; Specific qualifier value; Stimulus; Tissue Grafts; Tissues; Variant; Xenograft procedure; castration resistant prostate cancer; chromosome missegregation; cohort; drug-like compound; emerin; extracellular vesicles; genomic data; human data; human model; human tissue; in vivo; inhibitor; inhibitor therapy; men; micronucleus; neoplastic cell; novel; novel marker; novel therapeutic intervention; pressure; prognostic; programs; prostate cancer cell; prostate cancer metastasis; regeneration model; single cell analysis; small molecule; stemness; tissue regeneration; transcription factor; tumor growth; tumor heterogeneity

Contact PD/PI: Freeman, Michael R Project-004 (511) ABSTRACT (PROJECT 4) Aggressive prostate cancers (PC) exhibit phenotypic changes through a poorly-understood process termed “lineage plasticity (LP).” LP typically occurs as a result of secondary resistance to androgen receptor signaling inhibitor (ARSI) therapy and is identified by variant histology and emergence of stemness, neuroendocrine (NE) and epithelial-mesenchymal transition features. LP can be a driver of genome and chromosome instability (CIN). In the previous P01 cycle we were the first to report that the transcription factor ONECUT2 (OC2/HNF6β) is a master regulator that specifies an NE transcriptional program in certain castration-resistant prostate cancers (CRPC). OC2 suppresses androgen receptor (AR) target genes and acts as a survival factor. We developed a novel class of small molecule OC2 inhibitors that inhibit growth and metastasis of AR-V7-positive mCRPC xenografts. OC2 is thus a previously unknown driver of LP in aggressive PC that can be targeted with a drug- like compound. Evidence from genetically engineered mouse models and tissue regeneration models demonstrate that OC2 is upregulated under conditions that produce CIN. In the previous funding cycle we used model systems, genomics data, and studies of human PC tissues and circulating tumor cells (CTCs) to assemble evidence that CIN, OC2 activation, and nuclear shape instability (NSI) are shared features of both treatment- naïve de novo metastatic PC and mCRPC. These findings suggest these are inherent to one or more aggressive PC classes and may even occur in the absence of selection from ARSI. Using these observations as a scientific premise, we hypothesize that OC2, CIN, and NSI act coordinately to drive LP and PC lethality. The Specific Aims are: Aim 1. Determine the role of CIN in OC2-driven lineage plasticity. OC2 will be enforced in vivo in human PC tissue regeneration assays to determine whether OC2 activity is dependent on CIN and whether OC2 promotes LP, CIN or NSI. Graft tissues from intact and castrated mice will be analyzed for CIN, LP, and NSI using histologic, immunohistochemical, RNA expression profiling and bioinformatics methods. LP will be induced in human mCRPC 2D and 3D human models by hypoxia and bone marrow stromal secretions to determine whether these stimuli promote NSI and CIN. Aim 2. Identify mechanisms of NSI that promote lineage plasticity. Tissue regeneration assays will be used to determine whether NSI induced by silencing the nuclear membrane protein emerin (EMD) promotes CIN, LP, and OC2 activation. We will determine whether EMD silencing can elicit or cooperate with CIN to drive tumor growth, LP and castration resistance. Aim 3. Investigate OC2 activation, CIN and NSI in parallel across primary and metastatic tumor cell populations. An established single cell analysis approach will be used to determine whether CIN, NSI and OC2 activation co-exist in human PC cells isolated from de novo metastatic and mCRPC cases. Project Summary/Abstract Page 699 Contact PD/PI: Freeman, Michael R Project-004 (511)

联系PD/PI：Freeman，Michael R Project-004（511） 摘要（项目4） 积极的前列腺癌（PC）暴露的表型通过所谓的不理解的过程变化 “谱系可塑性（LP）。” LP通常是由于对雄激素受体信号传导的继发性而发生的 抑制剂（ARSI）疗法通过变异的组织学和干性，神经内分泌（NE）的出现来鉴定 和上皮 - 间质转变特征。 LP可以是基因组和染色体不稳定性的驱动力（CIN）。 在上一个P01周期中，我们第一个报告了转录因子OneCut2（OC2/HNF6β）是一个 指定在某些持cast割前列腺中指定NE转录程序的主调节器取消 （CRPC）。 OC2抑制雄激素受体（AR）靶基因，并作为生存因子。我们开发了一个 新型的小分子OC2抑制剂，这些抑制剂抑制AR-V7阳性MCRPC的生长和转移 异种移植物。因此，OC2是侵略性PC中LP的先前未知驱动器 喜欢化合物。来自基因工程的小鼠模型和组织再生模型的证据 证明OC2在产生CIN的条件下进行了更新。在上一个资金周期中，我们使用了 模型系统，基因组数据以及人类PC组织和循环肿瘤细胞（CTC）的研究组装 CIN，OC2激活和核形状不稳定性（NSI）是两种处理的共同特征 - 幼稚的新转移PC和MCRPC。这些发现表明这些是一种或多个积极的遗传 PC类，甚至可能在没有ARSI选择的情况下发生。将这些观察结果作为科学 前提，我们假设OC2，CIN和NSI行为协调以推动LP和PC致死性。具体 目的是：目标1。确定CIN在OC2驱动的谱系可塑性中的作用。 OC2将在体内执行 人类PC组织再生测定法确定OC2活性是否取决于CIN以及OC2是否取决于CIN 促进LP，CIN或NSI。将分析来自完整和cast割小鼠的移植组织的CIN，LP和NSI 使用组织学，免疫组织化学，RNA表达分析和生物信息学方法。 LP将被诱导 在人类MCRPC 2D和3D人类模型中，通过缺氧和骨髓间隙来确定 这些刺激是否促进NSI和CIN。目标2。确定促进谱系可塑性的NSI机制。 组织再生测定法将用于确定是否通过使核膜沉默诱导NSI 蛋白质烯烃（EMD）促进CIN，LP和OC2激活。我们将确定EMD沉默是否可以 引起或辅导CIN来推动肿瘤的生长，LP和cast割抵抗。目标3。调查OC2 激活，CIN和NSI在原发性和转移性肿瘤细胞种群中并联。一个已建立的单曲 细胞分析方法将用于确定人类PC中CIN，NSI和OC2激活是否共存 从从头转移和MCRPC病例中分离出来的细胞。 项目摘要/摘要页面699 联系PD/PI：Freeman，Michael R Project-004（511）