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Metastasis of PTEN Mutant Prostate Cancer

PTEN突变前列腺癌的转移

基本信息

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
项目类别：
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

项目摘要

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.

据估计，2020年将有19万例新诊断，前列腺癌（PC）是第二常见的肿瘤在美国，男性癌症是男性癌症死亡的第二大原因。大约三分之一的 50岁以上的男性显示出这种肿瘤的组织学证据，但只有十分之一会被诊断出来具有临床意义的PC。局限性PC的治疗选择是有效的，然而，转移性PC是一个尚未解决的问题。因为标准抗雄激素治疗总是导致不治之症复发。PTEN-TP 53丢失是人致死性转移性PC的最重要事件，如PCF/SU 2C国际前列腺癌梦之队（Armenia等人，2018年），并确认了20年的在鼠标中的功能PC建模。该项目的中心目标是了解是什么导致PTEN突变型惰性前列腺癌（PC），转移到身体的不同部位并杀死病人虽然PCF/SU 2C报告了PTEN缺失与TP 53缺失的显著相关性，但与PTEN显著共突变的其他基因的定义仍然是个问题重要的是，这些基因可以指出驱动转移的途径和原则和/或治疗抗性。我们的目标是解决这个问题，结合单细胞分析患者转移功能遗传学和小鼠致死性转移的3D全器官成像的快速尸检样品。我们使用了一种高度易变性的基因工程小鼠（GEM）模型，癌症，称为RapidCaP。在约70%的Pten/Trp 53突变型RapidCaP中观察到自发进展为致死性转移，这表明一个关键的随机先锋事件，无痛转移逃逸，类似于导致去势治疗后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时，已经涉及数千或数百万个细胞。在目标1中，我们揭示，分离和分析单个先锋细胞的空间和时间。我们将联合收割机RapidCaP与连续双光子断层扫描（STPT），它使我们能够以单细胞分辨率对整个器官进行成像，构建一个3D地图的时间进程的逃避无痛和转移复发后的治疗。这指导我们分离细胞类型，然后作为逃逸或复发的先驱细胞的验证代理。通过目标2，我们通过对人类快速尸检样本的单细胞全基因组分析，解决了PTEN共突变的僵局，并确定了与PTEN共缺失的基因。我们根据已经分离的先驱细胞在体外的综合功能分子探测的基础上优先考虑候选人。通过目标3，我们开发了两个新的建模平台，用于更灵活地验证候选基因和逃避无痛和复发去势治疗背后的原理。