Project 5

项目概述（见说明）：本项目研究肿瘤抑制基因（TSG）网络及其破坏如何影响恶性行为。最初基于其观察到癌基因可以激活p53促进细胞凋亡，我们的早期工作包括研究p53驱动细胞凋亡的机制，以及p53效应物的抑制或不受调节的生存信号在促进肿瘤发生过程中如何被规避。在上一个资助周期中，我们发现了几种新的致癌基因诱导的细胞凋亡调节因子，这些调节因子有助于肿瘤的发生，并验证了细胞存活的翻译控制作为治疗靶点。利用我们与Greg Hannon共同开发的诱导RNAi技术，我们还发现肿瘤中内源性p53的再激活可以根据不同的环境触发细胞凋亡或衰老，从而确定p53缺失在肿瘤维持中的作用。最后，利用项目中开发的小鼠模型的独特特征，我们通过候选基因测试和体内筛选，鉴定并验证了几个新的致癌基因和超过35个新的与人类癌症相关的tsg。展望未来，该项目将继续在生物和技术层面进行创新，采用更全面的方法研究肿瘤抑制因子，特别关注它们在胃肠道恶性肿瘤中的作用，并着眼于开发新的治疗靶点。具体而言，我们将在几种胃肠道恶性肿瘤中识别和表征新的TSG，研究极其常见但鲜为人知的大染色体缺失在癌症发展中的作用，探索关键TSG在肿瘤维持中的作用，并进行负选择RNAi筛选，以识别和表征TSG缺失造成的潜在脆弱性。在实验方面，我们将利用人类胃肠道癌症的基因组分析来为小鼠的功能研究提供信息，并实施一套新的RNAi工具和动物建模方法，以提高成本效益和分析速度。这些研究的成功完成将确定与人类胃肠道恶性肿瘤相关的新基因，并确定它们如何影响疾病行为。我们的努力也可能确定新的治疗靶点，以治疗TSG突变的癌症，否则很难利用治疗。为了实现这些目标，我们的项目将产生一个可以应用于其他基因和肿瘤类型的蓝图。我们的目标是更全面地了解肿瘤抑制网络，并确定与特定癌症基因型相关的治疗靶点。

Project 5: S. Lowe Tumor Suppression Hannon, Gregory J PROJECT SUMMARV (See instructions): This project studies tumor-suppressor gene (TSG) networks and how their disruption influences malignant behavior. Initially based on its observation that oncogenes can activate p53 to promote apoptosis, our early efforts involved studying mechanisms whereby p53 drives apoptosis and how suppression of p53 effectors or deregulated survival signaling can circumvent during promote tumorigenesis. Over the last funding cycle, we identified several new regulators of oncogene-induced apoptosis that contribute to tumorigenesis and validated translational control of cell survival as a therapeutic target. Taking advantage of inducible RNAi technology we developed with Greg Hannon, we also showed that reactivation of endogenous p53 in tumors potently triggered apoptosis or senescence depending on context, thus establishing a role for p53 loss in tumor maintenance. Finally, exploiting unique features of the mouse models developed in the program we, through candidate gene testing and in vivo screens, identified and validated several new oncogenes and over 35 new TSGs that are relevant to human cancer. Moving forward, the project will continue to innovate at both the biological and technical levels, taking a more comprehensive approach towards studying tumor suppressors, with a particular focus on their action in gastrointestinal malignancies and an eye towards developing new therapeutic targets. Specifically, we will identify and characterize new TSGs in several gastrointestinal malignancies, study the role of extremely common but poorly understood large chromosomal deletions on cancer development, explore the action of key TSGs in tumor maintenance, and perform negative selection RNAi screens to identify and then characterize potential vulnerabilities created by TSG loss. Experimentally, we will take advantage of genomic analyses of human gastrointestinal cancers to inform functional studies in mice, and implement a suite of new RNAi tools and animal modeling approaches to increase the cost effectiveness and pace of our analyses. Successful completion of these studies will identify new genes relevant to human gastrointestinal malignancies and determine how they influence disease behavior. Our efforts may also identify new therapeutic targets for treating cancers with TSG mutations, which have otherwise been difficult to exploit therapeutically. In addressing these aims, our project will produce a blueprint that can be applied to other genes and tumor types. Our goal is to gain a more comprehensive understanding of tumor suppressor networks and identify therapeutic targets relevant to specific cancer genotypes.