The Yap-Tead transcriptional complex in Kras-induced Pancreatic Ductal Adenocarci

描述（由申请人提供）：胰腺导管腺癌（PDAC）是最致命的人类癌症之一，约95%的病例由Kras致癌突变驱动。因此，致癌Kras及其下游效应物在理论上是PDAC治疗干预的理想候选物。不幸的是，直接抑制致癌Kras或已知Ras效应子途径的尝试要么不成功，要么被证明无效。因此，有显着的兴趣，在确定新的下游效应致癌Kras信号转导 可以通过药物干预来治疗。我们最近发现雅普（Yes相关蛋白）是PDAC发展过程中致癌Kras信号传导的重要介质（手稿正在审查中）。在这项研究中，我们提出了一个多方面的努力，以确定通过雅普和它的转录伙伴Tead 1/2/3/4介导致癌Kras信号传导的机制，并确定是否雅普和Tead 1/2/3/4所需的PDAC的维护和转移。在目标1中，我们将确定连接致癌Kras的Yap-Tead转录复合物的信号转导事件。我们将集中于表征致癌Kras诱导的雅普转录后修饰如何影响雅普介导的转录和PDAC的发展。在目标2中，我们将使用经工程改造以诱导表达雅普短发夹RNA的原位小鼠模型来确定PDAC肿瘤维持和转移对雅普的需求。这些小鼠模型将验证雅普作为PDAC治疗靶点的潜力。在目标3中，我们将检验Tead 1/2/3/4与雅普协同作用以介导关键致癌Kras诱导基因的转录并支持PDAC在体外和体内的发展和进展的假设。总的来说，这些研究将为PDAC发病机制的分子机制提供重要的见解，为PDAC更有效的治疗策略打开大门。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human cancers and in ~95% of cases driven by oncogenic mutations of Kras. Therefore, oncogenic Kras and its downstream effectors are, in theory, ideal candidates for PDAC therapeutic intervention. Unfortunately, attempts to directly inhibit oncogenic Kras or known Ras effector pathways have been either unsuccessful or proven ineffective. As a result, there is significant interest in identifying novel downstream effectors of oncogenic Kras signaling that could be amenable to pharmacological intervention. We have recently identified Yap (Yes-associated-protein) as an essential mediator of oncogenic Kras signaling during PDAC development (manuscript currently under review). In this grant we propose a multi-faceted effort to identify the mechanism through which Yap and its transcriptional partners Tead1/2/3/4 mediate oncogenic Kras signaling and determine whether Yap and Tead1/2/3/4 are required for PDAC maintenance and metastasis. In Aim 1, we will identify the signal transduction events that connect oncogenic Kras to the Yap-Tead transcriptional complex. We will focus on characterizing how oncogenic-Kras-induced posttranscriptional modifications of Yap affects Yap-mediated transcription and PDAC development. In Aim 2, we will determine the requirement for Yap in PDAC tumor maintenance and metastases using orthotopic mouse models engineered to inducibly express Yap shRNAs. These mouse models will validate the potential of Yap as a therapeutic target for PDAC. In Aim 3, we will test the hypothesis that Tead1/2/3/4 function in concert with Yap to mediate the transcription of key oncogenic Kras-induced genes and support PDAC development and progression in vitro and in vivo. Collectively, these proposed studies will provide critical insights into the molecular mechanisms underlying PDAC pathogenesis, opening doors to more effective treatment strategies for PDAC.