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

这项建议的总体目标是描绘ZIP4激活的ZEB1依赖的机制 胰腺癌(PC)的转移。探讨其功能影响及其潜在机制。 这一途径对于了解肿瘤的生物学行为和研究肿瘤的进展和转移是至关重要的。 PC机 PC的死亡率是所有癌症中最高的，5年存活率低于8%。尽管在以下方面取得了进展 诊断方法的改进和靶向治疗的发展，总体存活率并未提高 近几十年来显著增加。了解PC的生物学，并识别新奇的东西是必要的 PC中的分子标记和治疗靶点，以开发更有效的治疗方法，减少 对这种毁灭性疾病的抗药性。在这个提案中，我们的目标是描述分子 关键的锌转运蛋白ZIP4和锌依赖的EMT样蛋白的功能机制 转录因子(EMT-TF)ZEB1在PC转移中的作用我们的初步数据表明，ZIP4促进 ZEB1通过调控PC的生长和转移。进一步的研究表明，这一新的 ZIP4-ZEB1轴上调整合素，进而介导整合素介导的细胞黏附、迁移和 入侵。我们将以这些发现为基础，进一步理解这一机制(S) Pc中潜在的ZIP4致癌功能。我们假设ZIP4通过一种 不同的信号通路导致EMT-TFZEB1的激活，这一途径代表了一种 治疗这种令人沮丧的疾病的新靶点。三个独立但又相互关联的具体目标是 提出了解决这一假设的建议。我们将确定ZIP4调节的ZEB1通路在 PC细胞。我们将确定ZIP4调节的ZEB1通路在两个独立的小鼠身上的影响 PC模型(异种原位移植模型和自发性模型)。我们还将描述信号通路 ZIP4下游激活PC中ZEB1依赖的整合素转录。 ZIP4激活的ZEB1上调代表了一种新的调控生长的信号通路， PC肿瘤的转移和耐药性。拟议的研究将有助于确定这一机制 调节这一致癌轴，了解PC进展和转移的生物学机制。两者都有 机制和功能研究是利用最先进的技术和遗传学提出的 经过改造的老鼠模型。从这项研究中获得的结果将产生重大影响，因为它们将 显著提高了我们对关键的锌转运蛋白和锌依赖的EMT-TFZEB1的理解 PC转移。

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.