Notch signaling in initiation and progression of pancreatic cancer

描述(申请人提供)：指导我们研究的总体假设是，最初部署在胚胎中的胰腺器官发生的分子调节因子仍然与成人疾病过程相关。在这些调控因子中，有一条是Notch信号通路，PI以前曾在胚胎环境中研究过该通路。根据最近NCI计划的公告，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在发育中的胰腺中起抑制分化的作用；尽管已经在人类胰腺癌中检测到Notch通路的激活，但其在那里的作用尚未确定。在这种疾病的小鼠模型中形成的癌前病变中也观察到缺口的激活，这种激活是由K-ras癌基因的激活驱动的。我们的初步证据表明，Notch的激活显著地使胰腺前体细胞对K-ras诱导的异型增生敏感，我们假设成人中的Notch信号促使去分化到类似于K-ras的前体细胞状态。在这里，我们提出了两个特定的目标来研究Notch信号在胰腺癌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，并确定这些信号通路是否协同促进癌前病变的形成。(2)我们将对完整的小鼠和培养的人胰腺癌细胞应用独立的功能丧失方法，确定在胰腺癌的发生、发展和维持过程中对持续Notch信号的需求。除了指导未来对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途径是人类药物抑制的潜在靶点。 公共卫生相关性：该提案试图将Notch信号通路作为治疗胰腺癌的潜在药物靶点。此外，它还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.