Pancreatic Cancer Metastasis

摘要 P01提案的总体目标是确定MUC16在促进胰腺功能方面的机制作用 癌症(PC)转移。众所周知，胰腺癌是一种致命性癌症，也是一种弥漫性肿瘤。 约45%至55%的患者在癌症扩散后被诊断为转移性疾病。这个 转移的分子机制尚不清楚。在癌细胞中去极化的粘蛋白表达 导致细胞间的黏附改变，生长因子受体信号的异常增强，上皮细胞到... 间充质转化与耐药。在我们最近的研究中，我们观察到MUC16/CA125是一种 膜结合的粘蛋白，我们观察到它在PC进展过程中异常过度表达，而NO 在正常胰腺组织中也有表达。同样，我们的合作研究表明， 胰腺癌中MUC16胞浆表达患者的预后明显较差 病人。基于这些研究和我们的初步结果，我们对该计划项目的一般假设是 MUC16-Cter介导的信号转导，MUC16突变引起的生物效应，以及MUC16- 诱导的代谢重编程有助于PC转移。为了检验这一假设，我们提出了三个 高度集成的项目，研究一种多结构域、多功能粘蛋白的机制 MUC16促进肿瘤转移。第一个项目将集中于MUC16及其C-C的作用和机制(S)。 PC转移性进展中的终端域。项目1将由巴特拉领导，他有26年的经验 有胰腺癌和粘蛋白生物学领域的经验。第二个项目将探讨 PC转移中膜结合和循环MUC16及其糖基化的突变形式这个项目 将由霍林斯沃斯领导，他在胰腺癌和粘蛋白领域拥有27年的经验 生物学。第三个项目将专注于MUC16介导的诱导PC转移的代谢重编程。 这个项目将由辛格领导，他在胰腺癌生物学领域拥有14年的经验。这个 项目得到两个科学核心的支持，以促进动物研究(核心B)，评估治疗 战略和支持临床和动物组织收集和分析(核心C)。此外，一个 提议设立行政和生物信息学核心(A)，以整合不同的项目、核心和 调查人员，提供协调的管理结构以及生物信息学和统计数据分析。 总体而言，这一P01计划建立在UNMC现有的胰腺癌研究持续优势的基础上 这是参与调查人员长期和富有成效的合作历史的结果。我们希望 明确MUC16介导的PC转移的新机制，为更好地治疗PC 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.