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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，到2020年，前列腺癌（PC）的新诊断病例为19万例，是第二大最常见的肿瘤