Role of PKC iota in metaplasia and initiation of pancreatic cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)是一种侵袭性的、高度致命的疾病，其特点是对传统疗法具有极强的耐药性。因此，有必要更好地了解驱动PDAC的信号通路，并为治疗这种疾病的分子靶向治疗确定新的潜在靶点。K-ras原癌基因在绝大多数PDAC中发生突变，是维持许多PDAC细胞转化表型所必需的。致癌K-ras在PDAC的发生和发展中也起着关键作用。癌基因K-ras在小鼠胰腺上皮细胞中的表达诱导导管上皮化生，继而形成癌前病变，小鼠胰腺上皮内瘤变(MPanINs)具有进展为PDAC的能力。这些观察结果强烈表明致癌的K-ras基因驱动了胰腺癌发生的多步骤过程。然而，治疗靶向致癌K-ras的努力并不成功，导致人们加紧努力寻找更适合治疗干预的K-ras关键下游效应因子。我们发现，在其他系统中已知的致癌K-ι下游效应蛋白--蛋白激酶Cι在人胰腺肿瘤中高表达，并且高表达与患者的生存不良有关。此外，我们还发现，表达癌基因K-ι的pDAC细胞的转化生长和致瘤性需要PKC-ras。PKCι至少部分地通过激活致癌的PKCι-RAC1-MEK/ERK1/2信号轴来驱动细胞的转化生长。基于这些观察和我们的初步数据，我们假设PKCι在致癌K-ras介导的pDAC的启动和进展中是必需的。我们进一步假设，PKCι/rac1-mek/erk1/2信号轴通过调节特定的致癌信号通路来驱动胰腺癌的发生。我们设计了三个相互关联的具体目标来检验这些假设。1)分析K-ras介导的化生所需的PKCι调控的信号转导机制。2)探讨PKCι在K-RasG12D介导的胰腺癌发生和体内mPanIN形成中的作用。3)研究PKCι在K-RasG12D介导的PDAC中的作用。由于PDAC患者预后不佳，NCI已将胰腺癌研究确定为优先资助项目。这些研究都是高度翻译的，与胰腺癌有100%的相关性，目的是描述K-ι介导的癌基因胰腺化生、mPanIN的形成和进展为胰腺癌的过程中对PKCmPAIN的需求。此外，我们还将描述PKCι在致癌过程中的分子机制(S)。这些研究的意义由于目前存在以PKCι为治疗靶点的能力而得到加强。因此，通过这些临床前研究获得的见解可能转化为PDAC患者的新治疗策略。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly lethal disease marked by extreme resistance to conventional therapies. Thus, there is a need to better understand the signaling pathways that drive PDAC, and to identify new potential targets for molecularly-targeted therapies to treat this disease. The K-ras proto-oncogene is mutated in the vast majority of PDAC and is necessary for the maintenance of the transformed phenotype of many PDAC cell lines. Oncogenic K-ras also plays a critical role in the initiation and progression of PDAC. Expression of oncogenic K-ras in mouse pancreatic epithelium induces ductal metaplasia, followed by formation of preneoplastic lesions, mouse pancreatic intraepithelial neoplasias (mPanINs) with the ability to progress to PDAC. These observations strongly suggest that oncogenic K-ras drives a multi-step process of pancreatic carcinogenesis. However, efforts to therapeutically target oncogenic K-ras have not been successful, leading to intensive efforts to identify critical downstream effectors of K-ras that are more amenable to therapeutic intervention. We have found that protein kinase C iota (PKCι), a known downstream effector of oncogenic K-ras in other systems, is highly over-expressed in human pancreatic tumors, and that high tumor PKCι expression correlates with poor patient survival. Furthermore, we have found that PKCι is required for the transformed growth and tumorigenicity of PDAC cells expressing oncogenic K-ras. PKCι drives transformed growth of PDAC cells, at least in part, through activation of an oncogenic PKCι-Rac1- MEK/ERK1/2 signaling axis. Based on these observations, and our preliminary data, we hypothesize that PKCι is required for oncogenic K-ras-mediated PDAC initiation and progression. We further hypothesize that the PKCι/Rac1-MEK/ERK1/2 signaling axis drives pancreatic carcinogenesis by regulating specific pro-carcinogenic signaling pathways. Three interrelated specific aims are designed to test these hypotheses. 1) To dissect the PKCι-regulated signaling mechanisms required for K-ras-mediated metaplasia. 2) To assess the role of PKCι in K-rasG12D-mediated initiation of pancreatic carcinogenesis and mPanIN formation in vivo. 3) To determine the role of PKCι in K-rasG12D-mediated PDAC. Due to the poor prognosis of PDAC patients, the NCI has identified pancreatic cancer research as a funding priority. The proposed studies are highly translational and 100% relevant to pancreatic cancer, with the goal of characterizing the requirement for PKCι in oncogenic K-ras-mediated pancreatic metaplasia, mPanIN formation and progression to PDAC. In addition, we will characterize the molecular mechanism(s) by which PKCι contributes to the carcinogenic process. The significance of these studies is enhanced by the fact that the ability to therapeutically target PKCι currently exists. Thus, insights gained through these pre-clinical studies may be translated into new treatment strategies for PDAC patients.