N-cadherin and Metastatic Dissemination

N-钙粘蛋白和转移性播散

基本信息

批准号：
8637459
负责人：
GLENN Lawrence RADICE
金额：
$ 16.86万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637459
关键词：
Adhesives Affect Alleles Animal Model Animals Behavior Benign Biological Assay Blood Circulation Cadherins Cancer Model Cancer Patient Cell Adhesion Cell Adhesion Molecules Cell Lineage Cell Surface Proteins Cell Surface Receptors Cell surface Cell-Cell Adhesion Cells Cessation of life Characteristics Data Disease Disseminated Malignant Neoplasm Distant E-Cadherin Embryonic Development Epithelial Epithelium Etiology Event Evolution Family Future Genetic Suppression Grant In Vitro Invaded Label Laboratories Lead Link Maintenance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Mediating Melphalan Mesenchymal Modeling Molecular Mus N-Cadherin Neoplasm Metastasis Organ Orphan Drugs Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Pharmaceutical Preparations Play Pre-Clinical Model Primary Neoplasm Process Property Proteins Reporter Resistance Role Rosa Signal Transduction Site Staging Stem cells System Testing Therapeutic Tissues Tumor Cell Invasion Tumor-Derived Up-Regulation adhesion receptor high risk in vivo inhibitor/antagonist interest melanoma mouse model neoplastic cell pancreatic cancer cells preclinical study public health relevance receptor expression self-renewal therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is an aggressive and deadly disease that is characterized by invasive, metastatic progression and profound resistance to conventional therapeutics. Changes in cell adhesion receptor expression accompany the transition from benign tumors to invasive, malignant cancer and the subsequent metastatic dissemination of tumor cells. The importance of these molecular changes in the etiology of tumor progression is not well understood. We discovered that interfering with the expression of the cell surface protein N-cadherin is sufficient to increase survival in a highly metastatic mouse model of pancreatic cancer. However, why these animals survive longer is poorly understood. In this exploratory R21 application, we will employ a cell lineage labeling system (RosaYFP allele) to follow the fate of the N-cadherin-deficient circulating pancreatic cancer cells (CPCs). Additionally, the YFP label will allow us to isolate and characterize the molecular and cellular properties of the CPCs in detail. We hypothesize that interfering with N-cadherin expression and/or function will disrupt the invasion metastasis cascade, thus validating N-cadherin as a therapeutic target for pancreatic cancer. To establish the in vivo tracking system and test our hypothesis, we propose the following aims: (1) to determine whether N-cadherin haploinsufficiency affects the number of CPCs and their ability to metastasize. (2) To assess the survival and self-renewal properties of N-cadherin-deficient CPCs using a pancreatosphere assay. (3) To determine if the N-cadherin antagonist ADH-1 will decrease metastatic dissemination in the pancreatic cancer model. The utilization of the cell lineage marker YFP will enhance our understanding of the role of N-cadherin in metastasis in a robust preclinical model of pancreatic cancer.

描述（由申请人提供）：胰腺导管腺癌（PDA）是一种侵袭性且致命的疾病，其特征是侵袭性、转移性进展和对常规治疗的严重抵抗。细胞粘附受体表达的变化伴随着从良性肿瘤到侵袭性恶性癌症的转变以及随后的肿瘤细胞的转移性播散。这些分子变化在肿瘤进展病因学中的重要性尚不清楚。我们发现，干扰细胞表面蛋白 N-钙粘蛋白的表达足以提高高度转移性胰腺癌小鼠模型的存活率。然而，为什么这些动物能活得更久，人们却知之甚少。在此探索性 R21 应用中，我们将采用细胞谱系标记系统（RosaYFP 等位基因）来追踪 N-钙粘蛋白缺陷的循环胰腺癌细胞 (CPC) 的命运。此外，YFP 标签将使我们能够详细分离和表征 CPC 的分子和细胞特性。我们假设干扰 N-钙粘蛋白的表达和/或功能将破坏侵袭转移级联，从而验证 N-钙粘蛋白作为胰腺癌的治疗靶点。为了建立体内追踪系统并检验我们的假设，我们提出以下目标：（1）确定N-钙粘蛋白单倍体不足是否影响CPC的数量及其转移能力。 (2) 使用胰腺球测定评估 N-钙粘蛋白缺陷的 CPC 的存活和自我更新特性。 (3) 确定 N-钙粘蛋白拮抗剂 ADH-1 是否会减少胰腺癌模型中的转移扩散。细胞谱系标记物 YFP 的利用将增强我们对 N-钙粘蛋白在胰腺癌临床前模型中转移中的作用的理解。