Notch signaling in initiation and progression of pancreatic cancer

描述（由申请人提供）：指导我们研究的总体假设是，最初在胚胎中部署的胰腺器官发生的分子调节剂仍然与成人疾病过程相关。在这些调节因子中，Notch信号通路是PI先前在胚胎背景下研究的。基于最近NCI计划公告，寻求胰腺癌试点研究的建议（PA-06- 303），我们已经开始研究Notch信号在胰腺癌中的作用。Notch的作用是抑制发育中胰腺的分化;尽管在人类胰腺癌中已经检测到Notch途径的激活，但其在胰腺癌中的作用尚未确定。在该疾病的小鼠模型中形成的癌前病变中也观察到Notch激活，其由K-ras癌基因的激活驱动。我们的初步证据表明，Notch激活显着敏感的胰腺祖细胞K-ras诱导的发育不良，我们假设Notch信号在成人驱动去分化的祖细胞样状态，同样容易受到K-ras。在此，我们提出了两个具体的目的来研究Notch信号在胰腺癌的发生和发展中的作用。(1)我们将激活成年小鼠胰腺分化细胞中的K-ras和/或Notch信号传导，并确定这些途径是否协同促进癌前病变的形成。(2)我们将确定在胰腺癌的起始、进展和维持中持续Notch信号传导的需要，将独立的功能丧失方法应用于完整小鼠以及培养的人胰腺癌细胞。除了指导未来Notch和K-ras协同作用的机制研究外，我们预计这项工作的结果将具有相当大的临床意义，因为Notch途径是人类药理学抑制的潜在靶点。 公共卫生相关性：该提案旨在暗示或排除Notch信号通路作为胰腺癌的潜在药物靶点。此外，它将为这种致命的人类疾病的细胞和分子起源提供新的线索。本申请中描述的研究与胰腺癌100%相关。

DESCRIPTION (provided by applicant): The overall hypothesis that guides our research is that molecular regulators of pancreatic organogenesis, originally deployed in the embryo, remain relevant to adult disease processes. Among these regulators is the Notch signaling pathway, which the PI has previously studied in an embryonic context. Based on a recent NCI Program Announcement, seeking proposals for pilot studies in pancreatic cancer (PA-06- 303), we have begun to investigate the role of Notch signaling in pancreatic cancer. Notch acts to inhibit differentiation in the developing pancreas; although Notch pathway activation has been detected in human pancreatic cancer, its role there has not yet been determined. Notch activation is also observed in the precancerous lesions that form in a mouse model of this disease, driven by activation of the K-ras oncogene. Our preliminary evidence indicates that Notch activation dramatically sensitizes pancreatic progenitor cells to K-ras-induced dysplasia, and we hypothesize that Notch signaling in the adult drives dedifferentiation to a progenitor-like state that is similarly susceptible to K-ras. Here, we propose two Specific Aims to study the role of Notch signaling in initiation and progression of pancreatic cancer. (1) We will activate K-ras and/or Notch signaling in differentiated cells of the adult mouse pancreas, and determine whether the pathways synergistically promote the formation of precancerous lesions. (2) We will determine the requirement for continued Notch signaling in initiation, progression and maintenance of pancreatic cancer, applying independent loss-of-function approaches to intact mice as well as cultured human pancreatic cancer cells. In addition to guiding future mechanistic studies of Notch and K-ras synergy, we anticipate that the outcome of this work will be of considerable clinical relevance, given that the Notch pathway is a potential target for pharmacological inhibition in humans. Public Health Relevance: This proposal seeks to implicate or exclude the Notch signaling pathway as a potential drug target in pancreatic cancer. In addition, it will shed new light on the cellular and molecular origins of this deadly human disease. The research described in this application is 100% relevant to pancreatic cancer.