Pancreatic Cancer Metastasis

胰腺癌转移

• 批准号: 10203861
• 负责人: Surinder K. Batra
• 金额: $ 164.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203861
• 关键词: Actins; Animal Model; Animals; Autopsy; Bioinformatics; Biological; Biological Models; Biological Process; Biology; C-terminal; CA-125 Antigen; CRISPR/Cas technology; Cancer Biology; Cell Communication; Cell-Cell Adhesion; Chemosensitization; Clinical; Collaborations; Complex; Databases; Detection; Diagnosis; Diffuse; Disease; Distant; Drug resistance; Early Detection Research Network; Extracellular Matrix; Gene Expression Regulation; Genes; Goals; Growth Factor; Growth Factor Receptors; Histology; Integrin Binding; Integrins; Investigational Therapies; Knock-out; Ligands; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane; Metabolic; Metabolism; Molecular; Mucins; Mutate; Mutation; Neoplasm Metastasis; Oncogenic; PTK2 gene; Pancreas; Pathway interactions; Patients; Process; Prognosis; Program Research Project Grants; Property; Protein Isoforms; Receptor Signaling; Recording of previous events; Research Personnel; Resource Sharing; Role; STAT3 gene; Signal Pathway; Signal Transduction; Site; Specimen; Statistical Data Interpretation; Structure; Testing; The Cancer Genome Atlas; Therapeutic; Tissue Banks; Tissues; Transgenic Mice; animal tissue; anticancer research; autocrine; base; c-myc Genes; cancer cell; cell motility; epithelial to mesenchymal transition; experience; extracellular; glucose uptake; glycosylation; in vivo; ineffective therapies; mutant; neoplastic cell; novel; overexpression; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; paracrine; programs; treatment strategy; tumor; tumor progression

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.

抽象的 该 P01 提案的总体目标是确定 MUC16 在促进胰腺功能中的机制作用 癌症（PC）转移。众所周知，胰腺癌是致命的癌症之一，也是一种弥漫性癌症。 转移性疾病，大约 45% 至 55% 的患者在癌症扩散后被诊断出来。这 对转移的分子机制知之甚少。癌细胞中粘蛋白表达去极化 有助于改变细胞间粘附、生长因子受体信号传导的异常增强、上皮细胞间的 间质转化和耐药性。在我们最近的研究中，我们观察到 MUC16/CA125 是一种 膜结合粘蛋白，我们观察到它在 PC 进展过程中异常过度表达，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 MUC16胞浆表达的胰腺癌患者预后明显较差 患者。根据这些研究和我们的初步结果，我们对该计划项目的总体假设是 MUC16-Cter 介导的信号传导、MUC16 突变产生的生物效应以及 MUC16- 诱导的代谢重编程有助于 PC 转移。为了检验这个假设，我们提出了三个 高度集成的项目，研究多域、多功能粘蛋白的机制 MUC16 促进转移。第一个项目将重点关注 MUC16 及其 C- 的作用和机制 PC 转移过程中的终末域。项目 1 将由 Batra 领导，他拥有 26 年的行业经验。 在胰腺癌和粘蛋白生物学领域拥有丰富的经验。第二个项目将探讨以下角色： 膜结合和循环 MUC16 的突变形式及其在 PC 转移中的糖基化。本项目 将由 Hollingsworth 领导，他在胰腺癌和粘蛋白领域拥有 27 年的经验 生物学。第三个项目将重点关注 MUC16 介导的诱导 PC 转移的代谢重编程。 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。这 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 策略并支持临床和动物组织采集和分析（核心 C）。另外，一个 行政和生物信息学核心（A）旨在整合不同的项目、核心和 研究人员，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，该 P01 计划建立在 UNMC 现有的胰腺癌研究方面的持续优势之上 这是参与研究人员长期而富有成效的合作历史的结果。我们希望 定义了 MUC16 介导的 PC 转移的新机制，这将为更好地管理 PC 转移铺平道路 这种致命的疾病。