The role of EGFR signaling in progression of Kras-induced pacreatic tumors

项目概述：肿瘤发生的过程通常是由多个连续的遗传和表观遗传变化引起的，这些变化影响了许多细胞过程，包括肿瘤的生长、存活、侵袭性和转移能力。胰腺导管腺癌是胰腺的原发性癌症，与Kras基因的激活突变、多种肿瘤抑制基因的缺失以及表皮生长因子受体（EGFR）信号成分的表达增加有关。了解这些事件如何影响肿瘤发生，对于开发针对肿瘤生长、生存和转移的最关键成分的治疗方法至关重要。此外，了解哪些遗传或表观遗传事件发生在肿瘤发生的早期，可能会导致早期检测胰腺癌的生物标志物。小鼠模型最近描述了Kras突变作为胰腺肿瘤发生的一个强有力的启动器。除了Kras突变外，大多数胰腺腺癌表达异常高水平的与EGFR结合的生长因子以及高水平的EGFR本身。由于这种情况在人类肿瘤和早期前体病变中普遍存在，我们假设EGFR信号传导有助于胰腺肿瘤的早期发展。我们将通过两种方式验证这一假设，通过增加或减少EGFR信号与Kras癌基因的激活，使用胰腺导管腺癌的小鼠模型。我们将通过对生长因子HB-EGF的转基因过表达来增加EGFR信号，并通过使用EGFR基因突变的小鼠来减少EGFR信号。这些实验将表明肿瘤发生的哪个阶段受EGFR信号的影响，并确定EGFR是否以及何时是胰腺癌患者合适的化疗靶点。这项工作也将为进一步研究EGFR在胰腺肿瘤发生中的作用和调控机制奠定基础。相关性：胰腺癌是这个国家癌症死亡的第五大原因。这一方面是由于早期癌症难以发现，另一方面是由于这种癌症对传统疗法难以治愈。本文提出的研究通过研究EGFR信号在胰腺癌小鼠模型中的肿瘤发生作用，来研究EGFR信号作为潜在的生物标志物和/或治疗靶点。

DESCRIPTION (provided by applicant): Project Summary: The process of tumorigenesis generally results from multiple, sequential genetic and epigenetic changes that affect a number of cellular processes including growth, survival, invasiveness, and metastatic capabilities of the tumor. Pancreatic ductal adenocarcinoma, the primary cancer of the pancreas, is associated with activating mutations in the Kras gene, loss of multiple tumor suppressor genes, and increased expression of epidermal growth factor receptor (EGFR) signaling components. Understanding how each of these events affects tumorigenesis is essential to developing treatment that will target the most critical components of tumor growth, survival, and metastasis. Furthermore, understanding which genetic or epigenetic events occur early in tumorigenesis may lead to biomarkers for earlier detection of pancreatic cancer. Mouse models have recently delineated Kras mutation as a potent initiator of pancreatic tumorigenesis. In addition to Kras mutation, the majority of all pancreatic adenocarcinomas express abnormally high levels of the growth factors that bind to EGFR as well as high levels of EGFR itself. Due to this prevalence in human tumors and in early precursor lesions, we hypothesize that EGFR signaling contributes to early stages in pancreatic neoplasia. We will test this hypothesis in two ways, by increasing or by decreasing EGFR signaling in conjunction with activation of the Kras oncogene, using mouse models of pancreatic ductal adenocarcinoma. We will increase EGFR signaling via transgenic overexpression of the growth factor HB-EGF, and we will decrease EGFR signaling by using mice with a mutation in the Egfr gene. These experiments will indicate what stage of tumorigenesis is affected by EGFR signaling as well as determining if and when EGFR is an appropriate chemotherapeutic target in pancreatic cancer patients. This work will also lead to further studies on the mechanisms of EGFR action and regulation in pancreatic tumorigenesis. Relevance: Pancreatic cancer is the 5th leading cause of cancer deaths in this country. This is due both to difficulty in detecting early stage cancers and to this cancer being refractory to traditional therapies. The studies proposed here investigate EGFR signaling as a potential biomarker and/or therapeutic target, by studying its effects on tumorigenesis in a mouse model of pancreatic cancer.