Mechanisms of Prostate Cancer Metastasis

前列腺癌转移的机制

基本信息

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
项目类别：
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

项目摘要

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）侵袭性前列腺癌 (PC) 通过一个鲜为人知的过程表现出表型变化，称为 “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抵抗而发生的。” 抑制剂（ARSI）疗法，并通过变异组织学和干性、神经内分泌（NE）的出现来识别 LP 可能是基因组和染色体不稳定 (CIN) 的驱动因素。在之前的P01周期中，我们第一个报道了转录因子ONECUT2（OC2/HNF6β）是一个在某些去势抵抗性前列腺癌中指定 NE 转录程序的主调节因子 (CRPC)。我们开发了一种抑制雄激素受体 (AR) 靶基因并充当生存因子的药物。新型小分子 OC2 抑制剂，可抑制 AR-V7 阳性 mCRPC 的生长和转移因此，OC2 是侵袭性 PC 中以前未知的 LP 驱动因素，可以用药物来靶向。来自基因工程小鼠模型和组织再生模型的证据。证明 OC2 在产生 CIN 的条件下上调，在我们使用的上一个融资周期中。模型系统、基因组学数据以及对人类 PC 组织和循环肿瘤细胞 (CTC) 进行组装的研究有证据表明 CIN、OC2 激活和核形状不稳定 (NSI) 是两种治疗的共同特征这些研究结果表明，这些是一种或多种侵袭性固有的转移性 PC 和 mCRPC。 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依据。前提是，我们让 OC2、CIN 和 NSI 协调行动来驱动 LP 和 PC 的杀伤力。目标是：目标 1. 确定 CIN 在 OC2 驱动的谱系可塑性中的作用，OC2 将在体内强制执行。人 PC 组织再生测定以确定 OC2 活性是否依赖于 CIN 以及 OC2 是否促进 LP、CIN 或 NSI 将分析来自完整小鼠和去势小鼠的移植组织的 CIN、LP 和 NSI。使用组织学、免疫组织化学、RNA 表达谱和生物信息学方法诱导 LP。在人类 mCRPC 2D 和 3D 人类模型中通过缺氧和骨髓基质分泌物来确定这些刺激是否会促进 NSI 和 CIN。目标 2. 确定 NSI 促进谱系可塑性的机制。组织再生测定将用于确定是否通过沉默核膜诱导 NSI emerin 蛋白 (EMD) 促进 CIN、LP 和 OC2 激活我们将确定 EMD 沉默是否可以。引发或配合 CIN 驱动肿瘤生长、LP 和去势抵抗。目标 3. 研究 OC2。激活、CIN 和 NSI 在原发性和转移性肿瘤细胞群中并行进行。细胞分析方法将用于确定 CIN、NSI 和 OC2 激活是否在人类 PC 中共存从新发转移和 mCRPC 病例中分离出的细胞。项目摘要/摘要第 699 页联系 PD/PI：Freeman、Michael R Project-004 (511)