AR variant regulation during EMT and disease progression

EMT 和疾病进展期间的 AR 变异调控

• 批准号: 9319233
• 负责人: Kathryn Ware
• 金额: $ 6.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319233
• 关键词: Acetates; Address; Affinity Chromatography; Alternative Splicing; Androgen Receptor; Biological Markers; Cancer Biology; Cancer Etiology; Cancer Patient; Castration; Cell Line; Cells; Cessation of life; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coupling; Data; Development; Disease; Disease Progression; Disseminated Malignant Neoplasm; Drug resistance; Ectopic Expression; Engineering; Epithelial; Feeds; Genes; Genetic Transcription; Goals; Health; In Vitro; Investigation; Lead; Ligand Binding Domain; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Marker Discovery; Mass Spectrum Analysis; Measures; Mesenchymal; Metastatic Prostate Cancer; Metastatic to; Mission; Molecular; Molecular Target; N-Cadherin; Neoplasm Circulating Cells; Neoplasm Metastasis; Nuclear; Patients; Phenotype; RNA; RNA Splicing; Recruitment Activity; Regulation; Research; Research Design; Resistance; Signal Transduction; Snails; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Trans-Activators; Transcriptional Activation; Transcriptional Regulation; Transitional Cell; Up-Regulation; Variant; Vimentin; abiraterone; base; cancer biomarkers; cancer cell; cancer diagnosis; cancer therapy; castration resistant prostate cancer; cell motility; circulating biomarkers; clinically significant; epithelial to mesenchymal transition; feeding; gene induction; hormone therapy; in vivo; insight; men; migration; mortality; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pre-clinical; programs; promoter; prostate cancer cell; public health relevance; receptor expression; response; success; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor progression

 DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related mortality in men. Prostate cancer is responsible for over 80 deaths per day in the US, almost uniformly due to complications associated with metastasis. Understanding this metastatic propensity is of paramount clinical importance and critical to developing new therapies. The androgen receptor (AR) is a key gene involved in prostate cancer biology. AR-V7 is an alternatively spliced variant that lacks the ligand-binding domain. Importantly, expression of AR-V7 is associated with both therapeutic resistance and metastatic disease. Therefore, understanding the mechanism of AR-V7 creation and its contribution to metastatic disease is of high clinical significance and will lead to the development of new therapeutic targets. Objective: The goal of this proposal is to elucidate the mechanisms of upstream AR-V7 synthesis and downstream AR-V7 signaling, both of which may lead to new therapeutic strategies in prostate cancer. We hypothesize that induction of an epithelial-to-mesenchymal transition (EMT) alters AR transcription and alternative splicing leading to an increase in AR-V7 expression and AR-V7 signaling feeds-forward to promote a drug-resistant and highly metastatic cancer. Specific aims: We propose to: (1) examine the mechanism by which EMT induces AR-V7 expression; (2) unravel the mechanism(s) by which AR-V7 functionally impacts epithelial plasticity; and (3) measure and correlate the proportion of patients that express AR-V7 and EMT biomarkers in circulating tumor cells from metastatic prostate cancer patients progressing on AR-targeted therapies. Study design: For aim 1, we will systematically dissect the mechanisms of the transcriptional regulation and alternative splicing of AR-V7 during EMT induction. For aim 2, we will identify novel AR-V7-specific targets, measure the functional impact of AR-V7 both in vitro and in vivo on migration, invasion and metastasis and determine the mechanism by which AR-V7 induces distinct-targets involved in promoting metastatic disease. For aim 3, we will utilize AR-V7 status and RNA-seq data to measure and correlate AR-V7 expression with EMT biomarkers from circulating tumor cells isolated longitudinally from metastatic prostate cancer patients. Cancer relevance: The success of this research plan will advance the field of metastatic prostate cancer by identifying unique candidates to target AR-V7-driven prostate cancer and lead to the discovery of markers that can be measured clinically to better select successful treatments for prostate cancer patients. By providing insights into the molecular understanding of AR-V7-driven prostate cancer, this proposed research is directly relevant to the mission to eliminate cancer as a major health problem.

 描述（由适用提供）：前列腺癌是最常见的癌症，也是男性癌症相关死亡率的第二大原因。在美国，前列腺癌每天造成80多人死亡，几乎均匀，这是由于与转移相关的并发症。了解这种转移性倾向至关重要，对于开发新疗法至关重要。雄激素受体（AR）是参与前列腺癌生物学的关键基因。 AR-V7是缺乏配体结合域的剪接变体。重要的是，AR-V7的表达与治疗性耐药性和转移性疾病均相关。因此，了解AR-V7创造的机制及其对转移性疾病的贡献具有很高的临床意义，并将导致新的治疗靶标的发展。目的：该提案的目的是阐明上游AR-V7合成和下游AR-V7信号的机制，这两者都可能导致前列腺癌中新的治疗策略。我们假设上皮到间质转变（EMT）的诱导会改变AR转录和替代剪接，从而导致AR-V7表达和AR-V7信号源增加，从而促进抗药性和高度转移性癌症。具体目的：我们建议：（1）检查EMT诱导AR-V7表达的机制； （2）阐明AR-V7在功能上影响上皮可塑性的机制； （3）测量并将表达AR-V7和EMT生物标志物的患者比例与来自转移性前列腺癌患者循环肿瘤细胞的患者的比例相关联。研究设计：对于AIM 1，我们将系统地剖析EMT诱导过程中AR-V7的转录调控和替代剪接的机制。对于AIM 2，我们将确定新型的AR-V7特异性靶标，测量体外和体内AR-V7对迁移，入侵和转移的功能影响，并确定AR-V7诱导促进转移性疾病涉及的不同目标的机制。对于AIM 3，我们将利用AR-V7状态和RNA-Seq数据来测量和将AR-V7表达与从转移性前列腺癌患者纵向分离的循环肿瘤细胞中的EMT生物标志物相关联。癌症相关性：该研究计划的成功将通过识别独特的候选者来靶向AR-V7驱动的前列腺癌，并导致发现标记物，从而在临床上进行临床测量以更好地选择前列腺癌患者的成功治疗方法，从而推进前列腺癌的领域。通过提供对AR-V7驱动的前列腺癌的分子理解的见解，这项拟议的研究与消除癌症作为主要健康问题的使命直接相关。

项目成果

Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells.

• DOI: 10.3791/55520
• 发表时间: 2017-04
• 期刊: Journal of visualized experiments : JoVE
• 作者: Kathryn E. Ware;S. Gilja;Shenghan Xu;Samantha Shetler;M. Jolly;Xue-Yang Wang;Suzanne Bartholf Dewitt;Alexander J. Hish;Sarah Jordan;W. Eward;H. Levine;A. Armstrong;Jason A. Somarelli