Role of Zinc Dependent EMT-Transcription Factors (EMT-TF) in Pancreatic Cancer Metastasis

锌依赖性 EMT 转录因子 (EMT-TF) 在胰腺癌转移中的作用

• 批准号: 10434839
• 负责人: MIN LI
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434839
• 关键词: Address; Biological Assay; Biology; Cell Adhesion; Cells; Complex; Data; Development; Diagnostic Procedure; Disease; Drug resistance; Foundations; Gene Expression Regulation; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Growth; Human; Integrin-mediated Cell Adhesion Pathway; Integrins; KPC model; Knock-out; Luciferases; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediating; Methodology; Modeling; Molecular; Neoplasm Metastasis; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Property; Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Survival Rate; Technology; Transcriptional Regulation; Tumor Biology; Up-Regulation; Xenograft procedure; Zinc; cell motility; diagnostic strategy; effective therapy; gemcitabine; improved; knock-down; method development; migration; molecular marker; mortality; mouse model; new therapeutic target; novel; novel diagnostics; novel marker; novel therapeutics; overexpression; pancreatic cancer cells; pancreatic cancer model; promoter; targeted treatment; therapeutic target; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis; zinc-binding protein

The overall objective of this proposal is to delineate the mechanism of ZIP4-activated ZEB1-dependent metastasis in pancreatic cancer (PC). Investigating the functional impact and the underlying mechanism of this pathway is critical to understand the biology and make inroads on the progression and metastasis of PC. PC has the highest mortality rate of any cancer, with a 5-year survival rate below 8%. Despite progress in improved diagnostic methods and development of targeted therapies, overall survival has not improved significantly over recent decades. It is imperative to understand the biology of PC, and identify novel molecular markers and therapeutic targets in PC in order to develop more effective treatments and reduce drug resistance for this devastating disease. In this proposal, we aim to characterize the molecular mechanisms underlying the function of a key zinc transporter, ZIP4, and a zinc dependent EMT-like transcription factor (EMT-TF) ZEB1 in PC metastasis. Our preliminary data demonstrate that ZIP4 promotes PC growth and metastasis through the modulation of ZEB1. Further studies revealed that this newly identified ZIP4-ZEB1 axis upregulates integrins, and in turn integrin-mediated cell adhesion, migration and invasion. We will use these findings as a foundation to further our understanding of the mechanism(s) underlying ZIP4 oncogenic function in PC. We hypothesize that ZIP4 promotes PC metastasis through a distinct signaling pathway leading to the activation of an EMT-TF ZEB1, and this pathway represents a novel therapeutic target for this dismal disease. Three independent but interrelated specific aims are proposed to address this hypothesis. We will determine the impact of the ZIP4-regulated ZEB1 pathway in PC cells. We will determine the impact of the ZIP4-regulated ZEB1 pathway in two independent mouse models of PC (orthotopic xenograft and spontaneous models). We will also delineate the signaling pathway downstream of ZIP4-activated ZEB1-dependent transcription of integrins in PC. The ZIP4-activated ZEB1 upregulation represents a novel signaling pathway modulating the growth, metastasis, and drug resistance of PC tumors. The proposed studies will help define the mechanism regulating this oncogenic axis and understand the biology of the progression and metastasis of PC. Both mechanistic and functional studies are proposed using state-of-the-art technologies and genetically engineered mouse models. The results obtained from this study will be of high impact since they will significantly advance our understanding on a key zinc transporter and a zinc dependent EMT-TF ZEB1 in PC metastasis.

该提案的总体目标是阐明ZIP 4激活的ZEB 1依赖性机制 胰腺癌（PC）转移。调查功能影响和潜在机制， 这条通路对于理解生物学和对肿瘤的进展和转移的进展至关重要。 PC. PC是所有癌症中死亡率最高的，5年生存率低于8%。尽管取得了进展， 尽管诊断方法的改进和靶向治疗的发展，但总生存率并未改善 近几十年来，当务之急是了解PC的生物学， 分子标记和治疗靶点，以开发更有效的治疗方法， 对这种毁灭性疾病的耐药性。在这个建议中，我们的目标是表征分子 关键锌转运蛋白ZIP 4和锌依赖性EMT样蛋白的功能机制 转录因子（EMT-TF）ZEB 1在PC转移中的作用。我们的初步数据表明，ZIP 4促进 通过ZEB 1的调节PC的生长和转移。进一步的研究表明， 鉴定的ZIP 4-ZEB 1轴上调整联蛋白，进而上调整联蛋白介导的细胞粘附、迁移和凋亡。 入侵我们将以这些发现为基础，进一步了解其机制。 潜在的ZIP 4致癌功能。我们假设ZIP 4通过一种新的途径促进PC转移。 不同的信号通路导致EMT-TF ZEB 1的激活，并且该通路代表了一种新的信号通路。 这种令人沮丧的疾病的新的治疗目标。三个独立但相互关联的具体目标是 提出了解决这一假设。我们将确定ZIP 4调节的ZEB 1通路在 PC细胞。我们将在两个独立的小鼠中确定ZIP 4调节的ZEB 1通路的影响。 PC模型（原位异种移植和自发模型）。我们还将描绘信号通路 PC中ZIP 4激活的ZEB 1依赖性整合素转录的下游。 ZIP 4激活的ZEB 1上调代表了一种调节生长的新信号通路， 转移和耐药性。拟议的研究将有助于确定机制 调节这一致癌轴，并了解PC的进展和转移的生物学。两 机制和功能的研究提出了使用国家的最先进的技术和遗传 工程小鼠模型。从这项研究中获得的结果将具有很大的影响，因为它们将 显著地推进了我们对锌转运蛋白和锌依赖性EMT-TF ZEB 1的理解， PC转移。