Metastasis of PTEN Mutant Prostate Cancer

PTEN突变前列腺癌的转移

• 批准号: 10540005
• 负责人: Lloyd C Trotman
• 金额: $ 52.94万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540005
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Dimensional; Address; Age; Americas; Animals; Antiandrogen Therapy; Armenia; Autopsy; Back; Body part; Breeding; CRISPR/Cas technology; Candidate Disease Gene; Castration; Cell Culture Techniques; Cell Separation; Cells; Cessation of life; Clinical; Collaborations; Dependence; Development; Diagnosis; Disease; Dreams; Event; Frequencies; Gene Mutation; Generations; Genes; Genetic; Genetically Engineered Mouse; Goals; Histologic; Human; Image; Immunocompetent; In Vitro; Indolent; International; Lentivirus Vector; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Metastatic Prostate Cancer; Metastatic to; Microscopy; Modeling; Molecular; Molecular Probes; Mus; Mutate; Mutation; Nature; Neoplasm Metastasis; Nude Mice; Oncogenes; Organ; Organoids; PTEN gene; Pathway interactions; Patients; Penetrance; Pharmacology; Phenotype; Phosphotransferases; Positioning Attribute; Problem Solving; Prostate; Proxy; Receptor Protein-Tyrosine Kinases; Recurrent disease; Relapse; Reporting; Research; Resistance; Resolution; Role; Sampling; Signal Transduction; Site; Survivors; System; TP53 gene; Techniques; Testing; Therapeutic; Three-Dimensional Imaging; Time; Transplantation; Validation; Washington; base; candidate validation; cell type; cellular imaging; flexibility; genome analysis; genome sequencing; imaging platform; in vivo; in vivo Model; lead candidate; male; men; mutant; neoplastic cell; programs; prostate cancer model; single cell analysis; standard of care; tomography; tumor; tumor diagnosis; two-photon; upstream kinase; whole genome

With an estimated 190,000 new diagnoses in 2020, Prostate Cancer (PC) is the second most frequent tumor diagnosed in men and the second leading cause of male cancer deaths in America. Approximately one in three men over the age of 50 shows histological evidence of this tumor, however only one in ten will be diagnosed with clinically significant PC. Therapeutic options for localized PC are effective, however, metastatic PC is a yet incurable disease because standard of care anti-androgen therapy invariably results in incurable disease relapse. PTEN-TP53 loss is a most significant event of human lethal metastatic PC as summarized by the PCF/SU2C International Prostate Cancer Dream Team (Armenia et al., 2018) and confirmed by two decades of functional PC modeling in mouse. The central goal of this project is to understand what causes PTEN-mutant indolent prostate cancer (PC) to metastasize to different parts of the body and kill the patient. While the PCF/SU2C report significant association of PTEN loss with loss of TP53, the definition of further genes that are significantly co-mutated with PTEN has remained a problem. Importantly, such genes could point to pathways and principles that drive metastasis and/ or therapy resistance. We aim to solve this problem by combining single cell analysis of patient metastatic rapid autopsy samples with functional genetics and 3D whole organ imaging of lethal metastasis in mouse. We use a highly flexible genetically engineered mouse (GEM) model of lethal, endogenous metastatic prostate cancer, termed RapidCaP. Spontaneous progression to lethal metastasis is seen in ~70% of Pten/Trp53-mutant RapidCaP, suggesting a critical stochastic pioneer event that switches a Pten/ Trp53 null tumor cell from indolence to metastatic escape, similar to a critical pioneering event that causes relapse after castration therapy. However, classical approaches can only capture and reveal the time and physical nature of these pioneering events when already thousands or millions of cells are involved. In Aim 1, we reveal, isolate, and analyze single pioneer cells in space and time. We combine RapidCaP with serial two photon tomography (STPT), which allows us to image whole organs at single cell resolution and construct a 3D map of the time course of escape from indolence and of metastatic relapse after therapy. This guides our isolation of cell types that then serve as validated proxies for pioneer cells of escape or relapse. Through Aim 2, we solve the PTEN co-mutation impasse and define genes co-deleted with PTEN through single cell whole genome analysis of human rapid autopsy samples. We prioritize candidates based on comprehensive functional molecular probing of already isolated pioneer cells in vitro. Through Aim 3, we develop two new modeling platforms for more flexible validation of candidate genes and principles behind escape from indolence and relapse from castration therapy.

前列腺癌(PC)是第二常见的肿瘤，2020年估计有19万例新诊断 被诊断为男性癌症，是美国男性癌症死亡的第二大原因。大约三分之一的人 50岁以上的男性显示出这种肿瘤的组织学证据，但只有十分之一的人会被诊断出来 临床上有意义的fi不能PC。局限性PC的治疗方案是有效的，但转移性PC仍是一种 不治之症，因为标准的护理，抗雄激素治疗总是会导致不治之症复发。PTEN-TP53缺失是PCF/SU2C国际前列腺癌梦之队(亚美尼亚等人，2018年)总结的人类致命转移性PC中最重要的事件，fifi通过20年的研究总结了这一事件 鼠标中的PC建模功能。 这个项目的中心目标是了解是什么导致PTEN突变的惰性前列腺癌(PC) 转移到身体的不同部位并杀死病人。虽然PCF/SU2C的报告表明fi不能将PTEN的缺失与TP53的缺失联系起来，但对其他显著的与PTEN共突变的基因的检测可以fifi 一直是个问题。重要的是，这样的基因可能指向驱动转移的途径和原理。 和/或治疗抵抗。我们的目标是通过结合患者转移的单细胞分析来解决这个问题。 小鼠致死性转移的功能遗传学和三维全器官成像快速尸检标本。 我们使用fl高度可表达的基因工程小鼠(Gem)建立致死性、内源性转移性前列腺癌模型。 癌症，称为RapidCaP。在大约70%的Pten/Trp53突变RapidCaP中可以看到自发进展到致命转移，这表明一个关键的随机先驱事件将Pten/Trp53缺失的肿瘤细胞从 对转移逃逸的懒惰，类似于在去势治疗后导致复发的关键开创性事件。然而，经典的方法只能捕捉和揭示这些开创性事件的时间和物理性质，而这些事件已经涉及数千或数百万个细胞。 在目标1中，我们在空间和时间上揭示、分离和分析单个先锋细胞。我们将RapidCaP与 连续双光子断层扫描(STPT)，它允许我们以单细胞分辨率和 构建一张3D地图，显示摆脱懒惰和治疗后转移复发的时间进程。这 指导我们分离细胞类型，然后作为逃逸或复发的先锋细胞的有效替代品。 通过目标2，我们通过快速尸检标本的单细胞全基因组分析，解决了PTEN共突变僵局和DefiNe基因与PTEN共缺失的问题。我们根据已在体外分离的先锋细胞的全面功能分子探测来优先选择候选细胞。通过目标3，我们开发了两个 新的建模平台为更多的fl证实了候选基因和原理背后的逃脱懒惰和复发从阉割治疗。