Role of Nix in pancreatic ductal adenocarcinoma

Nix 在胰腺导管腺癌中的作用

基本信息

批准号：
9121778
负责人：
Brinda Alagesan
金额：
$ 3.34万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2019-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121778
关键词：
Ablation Adenocarcinoma Cell Adenoviruses Alleles Anabolism Area Autophagocytosis BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like Cancer Etiology Cancer Patient Cancer cell line Cell Proliferation Cell Survival Cells Cessation of life Characteristics Citric Acid Cycle Clinical Clinical Trials Cytoplasm Dependence Dependency Development Disease Doxycycline Drug Targeting Ductal Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Fatty Acids Genes Genetically Engineered Mouse Glucose Glycolysis Goals Hexosamines Homeostasis Human In Vitro KRAS2 gene Laboratories Lead Legitimacy MEKs Maintenance Malignant neoplasm of pancreas Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Mitochondria Mitochondrial Proteins Modeling Mus Mutation Oncogenic Organelles Organoids Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pentosephosphates Process Production Proteins RNA Recycling Role Signal Pathway Signal Transduction Small Interfering RNA System TP53 gene Testing Time Transplantation United States Warburg Effect Wild Type Mouse aerobic glycolysis base cancer cell cancer therapy cancer type cell type fatty acid metabolism glucose metabolism glucose uptake in vivo inhibition of autophagy inhibitor/antagonist interest knock-down macromolecule metabolic phenotype mouse model mutant neoplastic new therapeutic target novel oxidation oxidative damage pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis public health relevance small hairpin RNA success sugar targeted treatment therapeutic target three dimensional cell culture treatment strategy tumor tumor growth tumor initiation tumor metabolism tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth-leading cause of cancer-related death in the U.S. and remains a largely intractable disease. Nearly all cases of pancreatic ductal adenocarcinoma(PDAC) are characterized by activating mutations in the Kras gene. Attempts at pharmacological inhibition of Kras and its downstream signaling effectors in PDAC have so far been unsuccessful. Cancer cell metabolism has become a new area of interest for the development of targeted therapies. Through activation of various signaling pathways, oncogenic Kras induces a metabolic transformation that makes pancreatic cancer cells more reliant on glycolysis and less reliant on mitochondria-based metabolism. The proposed study focuses on Nix, a protein involved in mitochondrial maintenance and turnover, which might be responsible for the metabolic transformation seen in Kras-mutant cells. Our preliminary studies show that Nix is upregulated at the RNA and protein levels in murine pancreatic tumors. Additionally, ablation of Nix or Kras leads to a decrease in the number of mitochondria and the proliferative capacity of Kras-mutant, but not Kras wild-type, cancer cells. These results suggest the exciting possibility that Nix might be a legitimate drug target for the treatment of Kras-mutant pancreatic cancer. The proposed study will further elucidate the role of Nix in pancreatic cancer using genetically engineered mouse models and a novel pancreatic ductal organoid culture system. First, we will evaluate the metabolic consequences of Nix ablation using the organoid system. For the first time in vitro, this system will allow us to compare the metabolic phenotype of normal, pre-neoplastic and neoplastic pancreatic cells expressing or lacking Nix. Second, we will determine the role of Nix in pancreatic tumor intiation and maintenance using genetically engineered mouse models and an orthotopically transplanted organoid mouse model (respectively). We have crossed mice expressing a conditional Nix allele into our "KPC" mouse model, characterized by pancreas- specific expression of mutant Kras and mutant p53, to study the effects of Nix on pancreatic tumorigenesis. To study PDAC maintenance, we will transplant organoids infected with inducible short hairpin RNAs (shRNAs) targeting Nix into the pancreata of wildtype mice. These shRNAs will be induced after tumor formation in vivo to assess the effects of Nix knockdown on tumor maintenance. Results from these studies will not only validate the legitimacy of Nix as a suitable drug target for pancreatic cancer, but will also elucidate the role of Nix in the metaboli transformation of pancreatic cancer to provide a better understanding of this therapeutic target.

描述（由适用提供）：胰腺癌是美国与癌症相关死亡的第四个领先原因，并且仍然是一种很大的疾病。几乎所有胰腺导管腺癌（PDAC）的病例均以KRAS基因激活突变为特征。到目前为止，PDAC中对KRAS的药物抑制及其下游信号传导效应的尝试尚未成功。癌细胞代谢已成为靶向疗法发展的新领域。通过激活各种信号通路，致癌性KRA诱导了代谢转化，这使胰腺癌细胞对糖酵解的敏感性更高，对基于线粒体的代谢敏感。拟议的研究集中于Nix，Nix是一种参与线粒体维持和周转率的蛋白质，这可能导致KRAS突变细胞中看到的代谢转化。我们的初步研究表明，NIX在鼠胰腺肿瘤的RNA和蛋白质水平上进行了更新。此外，Nix或Kras的消融导致线粒体数量减少，KRAS突变体的增殖能力，但不能减少KRAS野生型癌细胞。这些结果表明，NIX可能是治疗KRAS突变胰腺癌的合法药物目标的令人兴奋的可能性。拟议的研究将进一步阐明Nix在胰腺癌中使用基因工程的小鼠模型和新型的胰管导管器官培养系统的作用。首先，我们将使用器官系统评估NIX消融的代谢后果。该系统首次将使我们能够比较表达或缺乏NIX的正常，肿瘤前和肿瘤胰腺细胞的代谢表型。其次，我们将使用一般工程的小鼠模型和原位移植的类肌动物小鼠模型来确定NIX在胰腺肿瘤感染和维持中的作用。我们已经将表达条件NIX等位基因的小鼠跨入了我们的“ KPC”小鼠模型，其特征是突变KRAS和突变体p53的胰腺特异性表达，以研究NIX对胰腺肿瘤发生的影响。为了研究PDAC维护，我们将以可诱导的短发蛋白RNA（SHRNA）的靶向NIX靶向NIX的诱导型类器官，将其靶向Wildtype小鼠的胰腺。这些shRNA将在体内形成肿瘤后诱导，以评估NIX敲低对肿瘤维持的影响。这些研究的结果不仅将验证NIX作为胰腺癌的合理药物靶标的合法性，而且还将阐明Nix在胰腺癌的代谢转化中的作用，以更好地理解这种治疗靶点。