N-cadherin and Metastatic Dissemination

描述（由申请人提供）：胰腺导管腺癌（PDA）是一种侵袭性和致命性疾病，其特征是侵袭性、转移性进展和对常规治疗的严重耐药性。细胞粘附受体表达的变化伴随着从良性肿瘤向侵袭性恶性肿瘤的转变以及随后的肿瘤细胞转移性播散。这些分子变化在肿瘤进展病因学中的重要性尚未得到很好的理解。我们发现，干扰细胞表面蛋白N-钙粘蛋白的表达足以增加胰腺癌高转移小鼠模型的存活率。然而，为什么这些动物能活得更久，人们却知之甚少。在这个探索性的R21应用中，我们将采用细胞谱系标记系统（RosaYFP等位基因）来跟踪N-钙粘蛋白缺陷循环胰腺癌细胞（CPC）的命运。此外，YFP标记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反应，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验证我们的假设，我们提出以下目标：（1）确定N-cadherin单倍不足是否影响CPC的数量及其转移能力。(2)使用胰球试验评估N-钙粘蛋白缺陷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性播散。细胞谱系标志物YFP的利用将增强我们对N-cadherin在胰腺癌的稳健临床前模型中的转移中的作用的理解。

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.