Mechanisms of Prostate Cancer Metastasis

前列腺癌转移的机制

• 批准号: 10473907
• 负责人: Michael R Freeman
• 金额: $ 45.24万
• 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/10473907
• 关键词: 3-Dimensional; Androgen Receptor; Aneuploidy; Bioinformatics; Biological Assay; Biological Models; Bone Marrow; Breast Cancer Cell; Castration; Cessation of life; Chromosomal Instability; Clonal Expansion; Diagnosis; Diagnostic; Disease; Down-Regulation; Epithelial; 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 Computations; Mus; Needle biopsy procedure; Neoplasm Circulating Cells; Neoplasm Metastasis; Neurosecretory Systems; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Patients; Pharmaceutical Preparations; 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; emerin; extracellular vesicles; genomic data; human data; human model; human tissue; in vivo; inhibitor/antagonist; men; 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）