Mechanism and treatment of PTEN mutant prostate tumorigenesis

PTEN突变型前列腺肿瘤发生机制及治疗

• 批准号: 8900211
• 负责人: Lloyd C Trotman
• 金额: $ 39.84万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900211
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Alleles; Animals; Award; Biological Models; Biology; Body part; Breeding; Bypass; Cell Proliferation; Cell Separation; Cells; Clinical; Complementary DNA; Complex; DNA; Disease; Disease Progression; Engineering; Event; Evolution; Feedback; Fluorescence; Funding; Gene Transfer; Genes; Genetic; Genetic Recombination; Genetically Engineered Mouse; Goals; Grant; Health; Histology; Human; Human Genetics; Indolent; Injection of therapeutic agent; Knock-out; Life; MYC gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Morphologic artifacts; Mus; Mutation; Neoplasm Metastasis; Oncogene Activation; Oncogenes; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Positioning Attribute; Problem Solving; Process; Prostate; Prostatic Diseases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Publishing; RNA Interference; RNA Sequences; Reporter; Research; Role; Sampling; Signal Transduction; System; TP53 gene; Technology; Testing; Time; Tumor Suppressor Proteins; Validation; Viral; Work; base; biobank; cancer genetics; cancer initiation; candidate validation; career; flexibility; genetic analysis; human data; human tissue; insight; interest; molecular pathology; mouse model; mutant; novel; preclinical study; prostate carcinogenesis; protein degradation; protein expression; response; senescence; success; targeted treatment; tool; transcriptome sequencing; transgene expression; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The central goal of this project is to understand what causes indolent prostate cancer to become life threatening and metastasize to different parts of the body. To understand this critical process, we explore genetic data from human prostate cancer studies and recreate prostate cancer in genetically engineered mice. Until recently, it has not been possible to generate simply detectable metastatic prostate cancer with this approach and complex breeding issues combined with the artifact of massive lethal primary disease have severely hampered progress. We have solved these problems by directly transferring genes of interest into mouse prostate, generating a model system that we term RapidCaP. Now, we are in position to dissect the relevance of new prostate cancer gene candidates in both the classic model of cancer initiation as well as in RapidCaP. We are using this new system to analyze metastasis on two levels. At the molecular level, we correlate changes in protein expression with histological features of metastasis. This analysis has revealed that, paradoxically, Pten/ p53-mutant prostate metastasis does not show activation of the downstream Akt oncogene, but activation of Myc instead. Thus, we expand the RapidCaP approach to study how these molecular changes affect the pro- pensity for metastatic spread of disease in an animal. To validate these findings in human, we collaborate with clinicians that perform the corresponding molecular histology analysis on human metastatic prostate cancer samples. At the same time, we interrogate metastasis biology by engineering novel genetic changes that may cause metastasis in the RapidCaP model, as well as by analysis of the spontaneously occurring alterations that are associated with metastasis. This project aims therefore to combine discovery of candidate metastasis genes with their functional validation in the RapidCaP model, which can afford us with fundamental insights into disease progression. The derived results and hypotheses will then be validated in human by clinical collaborators as part of their separate, independently funded project on their biobanked human tissues. As a case in point, we are validating the role of a candidate tumor suppressor, the Phlpp2 gene, which effectively blocks Akt signaling. We find that this gene is regulated by p53 as well as by the Myc oncogene, which appears to use it to shut down Akt in metastasis. Therefore, we will test the role of this p53- and Myc-regulated gene using the RapidCaP and classic conditional knockout approaches in combination with knockout cells, and the results will be validated by collaborators using their human tissue from a separately funded project. Thus, I strongly believe that our proposed work on developing this novel system for the study of endogenous prostate metastasis in mouse can greatly accelerate the research on how prostate cancers become lethal.

描述（由申请人提供）：该项目的中心目标是了解是什么导致惰性前列腺癌危及生命并转移到身体的不同部位。为了了解这一关键过程，我们探索了人类前列腺癌研究的遗传数据，并在基因工程小鼠中重现了前列腺癌。直到最近，用这种方法还不可能产生简单可检测的转移性前列腺癌，复杂的繁殖问题加上大规模致命原发性疾病的伪影严重阻碍了进展。我们通过将感兴趣的基因直接转移到小鼠前列腺中，生成了我们称之为 RapidCaP 的模型系统，解决了这些问题。现在，我们可以剖析新的前列腺癌候选基因在癌症发生的经典模型以及 RapidCaP 中的相关性。我们正在使用这个新系统从两个层面分析转移。在分子水平上，我们将蛋白质表达的变化与转移的组织学特征相关联。矛盾的是，该分析表明，Pten/p53 突变型前列腺转移并不显示下游 Akt 癌基因的激活，而是 Myc 的激活。因此，我们扩展了 RapidCaP 方法来研究这些分子变化如何影响动物疾病转移性传播的倾向。为了在人类中验证这些发现，我们与临床医生合作，对人类转移性前列腺癌样本进行相应的分子组织学分析。与此同时，我们通过在 RapidCaP 模型中设计可能导致转移的新基因变化，以及分析与转移相关的自发变化来探究转移生物学。因此，该项目的目标是将候选转移基因的发现与其在 RapidCaP 模型中的功能验证结合起来，这可以为我们提供对疾病进展的基本见解。然后，临床合作者将在人体中验证得出的结果和假设，作为其生物库人体组织独立资助项目的一部分。作为一个恰当的例子，我们正在验证候选肿瘤抑制基因 Phlpp2 基因的作用，该基因可有效阻断 Akt 信号传导。我们发现该基因受到 p53 以及 Myc 癌基因的调节，Myc 癌基因似乎利用它来关闭转移中的 Akt。因此，我们将测试这个p53-和的作用 Myc 调节基因使用 RapidCaP 和经典的条件敲除方法与敲除细胞相结合，结果将由合作者使用来自单独资助项目的人体组织进行验证。因此，我坚信，我们提出的开发这种用于研究小鼠内源性前列腺转移的新系统的工作可以极大地加速前列腺癌如何致死的研究。