Nrf2 Regulation of Ductal Pancreatic Cancer Etiology and Treatment Response

摘要：Nrf2对胰腺癌病因和治疗的调控 我们寻求利用胰腺导管腺癌(PDA)细胞的独特能力来抵抗 氧化应激有助于开发有效的治疗这种恶性肿瘤的方法。事实上，除了 患者通常表现为疾病的晚期，PDA的致命性在很大程度上 反映了他们的肿瘤对系统治疗的不良反应。我们之前曾报道过掌上电脑 小鼠模型的启动需要Nrf2转录因子，部分是通过Nrf2引导 许多基因的表达共同降低了细胞内的活性氧(ROS)。 其他人的进一步研究表明，NRF2或其结合蛋白Keap1发生了体细胞突变 通常在肺癌和乳腺癌中，导致NRF2途径的激活和药物的增加 抵抗。为了确定Nrf2如何促进PDA中的癌症形成和治疗耐药性，我们有 产生了新的条件模型，并开发了小鼠和人胰腺癌器官培养。 新的小鼠模型和有机化合物将服务于两个互补的目的：明确地确定 Nrf2是否仅以细胞固有方式促进PDA，并作为模型系统发挥作用 发现Nrf2效应通路并探索新的体内和体外治疗策略(目标1)。 因此，我们发现Nrf2通过其抗氧化功能来调节蛋白质翻译。 在PDA有机化合物中促进细胞增殖，我们将定义所涉及的生化机制和 确定它们是否代表新的治疗机会(目标2)。此外，我们已经确定了 PDA类有机物中新的非抗氧化相关Nrf2靶基因，我们将确定它们在PDA中的作用 发病机制(目标3)。我们的项目将利用定制的模型系统和最先进的质量 光谱学、基因组学、转录学和生物信息学方法，以确定新的介体 NRF2在PDA中的作用。在我们的工作中发现的NRF2效应通路和靶基因将被评估为 它们在PDA生物学和治疗耐药性中的个体重要性，以及最有希望的候选者 将使用遗传学和药理学方法在有机和小鼠模型中进行验证。我们 预计我们的结果将解释PDA肿瘤发生的基本方面，并将导致 为这种致命的恶性肿瘤开发更有效的治疗方法。

Abstract: Nrf2 Regulation of Ductal Pancreatic Cancer Etiology and Treatment We seek to leverage the unique capability of Pancreatic Ductal Adenocarcinoma (PDA) cells to resist oxidative stress towards the development of effective therapies for this malignancy. Indeed, in addition to the advanced stage of disease that patients typically have at presentation, the lethality of PDA largely reflects the poor response of their tumors to systemic therapeutics. We previously reported that PDA initiation in a mouse model required the Nrf2 transcription factor, in part through the ability of Nrf2 to direct the expression of many genes that collectively reduce intracellular reactive oxygen species (ROS). Additional work by others demonstrated that somatic mutations in NRF2 or its binding protein KEAP1 occur commonly in lung and breast cancer, resulting in the activation of the NRF2 pathway and increased drug resistance. To determine how Nrf2 promotes cancer formation and therapeutic resistance in PDA we have generated new conditional models and developed mouse and human pancreatic cancer organoid cultures. The new mouse models and organoids will serve two complementary purposes: to unequivocally determine whether Nrf2 functions solely in a cell intrinsic manner in promoting PDA, and as model systems to discover the Nrf2 effector pathways and explore new therapeutic strategies in vivo and ex vivo (Aim 1). Accordingly, we have found that Nrf2 regulates protein translation through its antioxidant function to promote cell proliferation in PDA organoids, and we will define the biochemical mechanisms involved and determine whether they represent new therapeutic opportunities (Aim 2). Furthermore, we have identified new, non-antioxidant related Nrf2 target genes in PDA organoids, and we will determine their role in PDA pathogenesis (Aim 3). Our project will utilize bespoke model systems and state-of-the-art mass spectrometric, genomic, transcriptomic, and bioinformatics methods in order to identify new mediators of Nrf2 function in PDA. Nrf2 effector pathways and target genes discovered in our work will be assessed for their individual importance in PDA biology and therapeutic resistance, and the most promising candidates will be validated in organoid and mouse models using genetic and pharmacological approaches. We anticipate that our results will explain fundamental aspects of oncogenesis in PDA and will lead to the development of more effective therapies for this deadly malignancy.