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.
Animal models of pancreatic cancer permit the rigorous exploration of disease pathogenesis, and provide systems to devise and test therapeutic strategies. The ability to interfere with the function of this cell surface receptor represents a promising therapeutic approach for metastatic cancer. It is our hope that these preclinical studies will lead to testing the N-cadherin antagonist ADH-1 in pancreatic cancer patients in the near future.
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