Pancreatic Cancer Metastasis

摘要 该P01提案的总体目标是定义MUC 16在促进胰腺癌中的机制作用。 癌（PC）转移。众所周知，胰腺癌是一种致命的癌症，也是一种弥漫性的恶性肿瘤。 转移性疾病，约45%至55%的患者在癌症扩散后诊断。的 转移的分子机制知之甚少。在癌细胞中去极化粘蛋白表达 有助于改变细胞-细胞粘附，生长因子受体信号传导的异常增强，上皮细胞- 间质转化和耐药性。在我们最近的研究中，我们观察到MUC 16/CA 125是一种免疫调节因子。 膜结合粘蛋白，我们已经观察到它的异常过度表达在PC的进展，而没有 在正常胰腺中观察到表达。同样，我们的合作研究表明， 胰腺癌中MUC 16胞浆表达的患者预后明显较差 患者根据这些研究和我们的初步结果，我们对该项目的一般假设是： MUC 16-Cter介导的信号传导、由MUC 16突变引起的生物学效应和MUC 16-Cter介导的信号传导， 诱导的代谢重编程有助于PC转移。为了验证这一假设，我们提出了三个 高度集成的项目调查的机制，多域，多功能粘蛋白 MUC 16促进转移。第一个项目将侧重于MUC 16及其C- 终末结构域在PC转移进展中的作用。项目1将由巴特拉领导，他有26年的经验， 在胰腺癌和粘蛋白生物学领域的经验。第二个项目将探讨 突变形式的膜结合和循环MUC 16及其在PC转移中的糖基化。这个项目 将由Hollingsworth领导，他在胰腺癌和粘蛋白领域有27年的经验 生物学第三个项目将集中在MUC 16介导的代谢重编程，诱导PC转移。 该项目将由Singh领导，他在胰腺癌生物学领域拥有14年的经验。的 项目由两个科学核心支持，以促进动物研究（核心B），评估治疗 支持临床和动物组织收集和分析（核心C）。此外， 行政和生物信息学核心（A）建议整合不同的项目，核心和 研究人员提供了一个协调的管理结构和生物信息学和统计数据分析。 总的来说，这个P01项目建立在UNMC胰腺癌研究的持续优势之上 这是参与调查者长期合作的结果。我们希望 定义MUC 16介导的PC转移的新机制，这将为更好地管理 这种致命的疾病。

ABSTRACT The overall goal of this P01 proposal is to define the mechanistic role of MUC16 in facilitating pancreatic cancer (PC) metastasis. It is well known pancreatic cancer is one of the lethal cancers and also a diffuse metastatic disease with approximately 45% to 55% of patients diagnosed after the cancer has spread. The molecular mechanisms of metastasis are poorly understood. In cancer cells depolarized mucin expression contributes to altered cell-cell adhesion, aberrant potentiation of growth factor receptor signaling, epithelial-to- mesenchymal transition, and drug resistance. In our recent study we have observed that MUC16/CA125 is a membrane bound mucin, and we have observed its aberrant overexpression during PC progression while no expression was observed in the normal pancreas. Similarly our collaborative study demonstrates that the prognosis of patients with MUC16 cytoplasmic expression was significantly poorer in pancreatic cancer patients. Based on these studies and our preliminary results our general hypothesis for the program project is that MUC16-Cter-mediated signaling, biological effects resulting from mutations of MUC16, and MUC16- induced metabolic reprograming contribute to PC metastasis. To test this hypothesis we are proposing three highly integrated projects investigating the mechanisms by which a multi-domain, muti-functional mucin MUC16 promotes metastasis. First project will focus on the role and mechanism(s) of MUC16 and its C- terminal domain in the metastatic progression of PC. Project 1 will be led by Batra, who has 26 years of experience in the field of pancreatic cancer and mucin biology. Second project will explore the roles of mutated forms of membrane bound and circulating MUC16 and its glycosylation in PC metastasis. This project will be led by Hollingsworth, who has 27 years of experience in the field of pancreatic cancer and mucin biology. Third project will focus on MUC16-mediated metabolic reprograming that induces PC metastasis. This project will be led by Singh, who has 14 years of experience in the field of pancreatic cancer biology. The projects are supported by two scientific cores to facilitate animal studies (Core B), evaluate therapeutic strategies and support clinical and animal tissue collection and analysis (Core C). Additionally, an Administrative and Bioinformatics Core (A) is proposed to integrate the different projects, cores and investigators, provide a coordinated management structure and bioinformatics and statistical data analysis. Overall this P01 program builds on the ongoing strengths in pancreatic cancer research that exist at UNMC and has resulted from a long and productive history of collaboration of participating investigators. We hope to define novel mechanisms of MUC16 mediated PC metastasis which will pave a way for better management of this lethal disease.