Non-Cell Autonomous Functions of N-cadherin in KRas-driven Preneoplastic Lesions

New York University School Of Medicine, New York NY

Investigators

Abstract

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth leading cause of death from cancer and has an extremely high mortality rate. Thus, a better understanding of pancreatic carcinoma initiation and disease progression is necessitated. Important features of this disease and its precursor lesions include activating mutations in KRas and the presence of a robust inflammatory response, both of which contribute to disease progression, and defining the microenvironmental link between KRas and pancreatic tumorigenesis represents a critical area of current research. Increased expression of N-cadherin has been reported in pancreatic ductal epithelial cells in response to activating KRas mutations (4-6). Recently, in addition to the conventional role of N-cadherin in mediating cell-cell adhesion N-cadherin has been shown to regulate cytokine production in prostate carcinoma cells, suggesting a potentially important but as of yet unrecognized function of N-cadherin in modulating the tumor microenvironment (7). Due to the well-established link between chronic inflammation and the development of premalignant lesions and adenocarcinoma of the pancreas (1), this novel function of N- cadherin is the subject of the project outlined herein. We propose the following Specific Aims to test the hypothesis that N-cadherin-associated cytokine modulation contributes to pancreatic tumorigenesis. Specific Aim 1: Identify cytokines and chemokines whose expression is linked to N-cadherin upregulation. This will involve defining changes the gene expression and protein levels of a panel of cytokines in mutant- KRas expressing pancreatic ductal epithelial cells in response to N-cadherin downregulation by shRNA. Targets will be validated in an in vivo model of KRas-driven development of premalignant pancreatic lesions. Specific Aim 2: Define the functional significance of N-cadherin-dependent changes in cytokine/chemokine expression. The effects of N-cadherin downregulation on cytokine production and development of KRas-driven pancreatic lesions will be assessed in an orthotopic implantation model. The effects of downregulation or blocking of N-cadherin-regulated cytokines on lesion development will also be determined. Specific Aim 3: Determine the mechanism by which N-cadherin dependent alterations in cytokine/chemokine expression could modulate neoplastic growth. The mechanistic consequences of N-cadherin mediated changes to cytokine expression and subsequent inflammatory cell recruitment will be analyzed in a combination of in vitro co-culture experiments and in vivo manipulations to particular immune components in the orthotopic model.