Atypical PKC signaling in lung cancer stem cells

描述（由申请人提供）：本项目的目标是阐明蛋白激酶C （PKC）信号机制，这些信号机制有助于肺癌的发生和维持，并将这些机制见解转化为更好的预后和治疗策略。我们最近发现了不典型的PKC？PRKCI基因是人类肺部的致癌基因此外，我们发现小鼠PKC？Prkci基因是体内由致癌性Kras诱导的肺肿瘤发生的最早步骤所必需的。具体来说，Prkci对于kras介导的细支气管肺泡干细胞（BASCs）的转化是必需的，BASCs是kras介导的肺肿瘤发生的假定起源细胞。基因破坏Prkci，或使用PKC9抑制剂金硫硫酸盐（ATM）治疗，可阻断kras介导的体外和体内BASC的扩增和形态转化，以及体内肺肿瘤的生长。初步结果表明Kras-， prkci介导的BASCs扩增涉及诱导多梳基因Bmi1。Bmi1是一种表观遗传染色质修饰因子/转录调节因子，与癌症干细胞的身份和自我更新有关。与Prkci一样，Bmi1也是kras介导的BASC扩增和肺肿瘤发生所必需的。基于这些初步数据，我们假设Prkci通过激活Bmi1信号通路，至少在一定程度上驱动kras介导的BASC转化和肺肿瘤发生。我们进一步假设类似的PKC？-Bmi1信号轴在人肺癌干细胞的维持、扩增和致瘤潜能中起关键作用。最后，我们假设ATM会有效抑制人肺癌干细胞的自我更新和致瘤潜能。我们将通过完成两个相互关联的具体目标来检验这些假设。在第一个目标中，我们会评估委员会的角色。-Par6-Ect2-Rac1信号轴在BASC转化中的作用及解析PKC？以及这些细胞中的Bmi1信号在目标2中，我们将确定PKC的作用？Bmi1信号在肺癌干细胞自我更新和肿瘤启动活性中的作用。我们将开发和表征一组来自原发性肺肿瘤的肺癌干细胞系。这些研究的完成将为致癌PKC的机制提供重要的新见解。该研究旨在增强我们对kras介导的肺肿瘤发生的理解，并评估一种针对肺癌干细胞中一个关键致癌途径的新型治疗剂的疗效。这些研究对PKC有重要意义。作为治疗靶点，以及利用ATM作为治疗肺癌的新疗法。

DESCRIPTION (provided by applicant): The goals of this project are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to lung cancer initiation and maintenance and translate these mechanistic insights into better prognostic and treatment strategies. We recently identified the atypical PKC? gene PRKCI as a human oncogene in the lung. Furthermore, we find that the mouse PKC? gene Prkci is required for the very earliest steps of lung tumorigenesis induced by oncogenic Kras in vivo. Specifically, Prkci is necessary for Kras-mediated transformation of bronchio-alveolar stem cells (BASCs), the putative cell of origin of Kras-mediated lung tumorigenesis. Genetic disruption of Prkci, or treatment with the PKC9 inhibitor aurothiomalate (ATM), blocks Kras-mediated expansion and morphological transformation of BASC in vitro and in vivo, and lung tumor growth in vivo. Preliminary results suggest that Kras-, Prkci-mediated expansion of BASCs involves induction of the polycomb gene Bmi1. Bmi1 is an epigenetic chromatin modifier/transcriptional regulator implicated in cancer stem cell identity and self-renewal. Like Prkci, Bmi1 is necessary for Kras-mediated BASC expansion and lung tumorigenesis. Based on these preliminary data, we hypothesize that Prkci drives Kras-mediated BASC transformation and lung tumorigenesis, at least in part, through activation of the Bmi1 signaling pathway. We further hypothesize that a similar PKC?-Bmi1 signaling axis plays a critical role in the maintenance, expansion and tumorigenic potential of human lung cancer stem cells. Finally, we hypothesize that ATM will effectively inhibit the self-renewal and tumorigenic potential of human lung cancer stem cells. We will test these hypotheses through completion of two interrelated specific aims. In Aim 1 we will assess the role of the PKC?-Par6-Ect2-Rac1 signaling axis in BASC transformation and dissect the mechanism of crosstalk between PKC? and Bmi1 signaling in these cells. In Aim 2 we will determine the role of PKC? and Bmi1 signaling in the self-renewal and tumor initiating activity of lung cancer stem cells. We will develop and characterize a panel of lung cancer stem cell lines from primary lung tumors. Completion of these studies will provide important new mechanistic insight into oncogenic PKC? signaling in putative lung cancer stem cells, enhance our understanding of Kras-mediated lung tumorigenesis, and assess the efficacy of a novel therapeutic agent that targets a critical oncogenic pathway in lung cancer stem cells. These studies have important implications for PKC? as a therapeutic target and for the use of ATM as a novel therapeutic for the treatment of lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the number one cause of cancer death in the United States. Protein kinase C??(PKC?) is an oncogene, prognostic marker and therapeutic target in lung cancer. This project will elucidate PKC? signaling mechanisms that drive lung cancer stem cell growth and tumor-initiating activity, and determine the efficacy of a novel PKC? inhibitor, aurothiomalate, to block lung cancer stem cell growth and tumorigenicity. Finally, this project will generate novel lung cancer stem cell resources from human lung cancer patients. These tissue resources will be invaluable in the assessment of novel therapeutics targeting these deadly cells.