Mechanism and treatment of PTEN mutant prostate tumorigenesis

描述（由申请人提供）：本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。为了理解这一关键过程，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建了前列腺癌。直到最近，还不可能用这种方法产生简单可检测的转移性前列腺癌，复杂的育种问题加上大量致命原发疾病的人工产物严重阻碍了进展。我们通过直接将感兴趣的基因转移到小鼠前列腺中来解决这些问题，产生了一个我们称之为RapidCaP的模型系统。现在，我们将在经典的癌症起始模型和RapidCaP中剖析新的前列腺癌候选基因的相关性。我们正在用这个新系统从两个层面分析转移。在分子水平上，我们将蛋白表达的变化与转移的组织学特征联系起来。该分析显示，Pten/ p53突变型前列腺转移并没有表现出下游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发生的变化，来询问转移生物学。因此，本项目旨在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，临床合作者将在其生物银行人体组织的单独、独立资助的项目中对所得结果和假设进行人体验证。作为一个恰当的例子，我们正在验证候选肿瘤抑制因子Phlpp2基因的作用，它可以有效地阻断Akt信号传导。我们发现这个基因受到p53和Myc癌基因的调控，Myc癌基因似乎利用它在转移过程中抑制Akt。因此，我们将测试p53- and的作用

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.