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.
Pancreatic adenocarcinoma is a leading cause of death from cancer with an extremely low 5-year survival rate (overall, less than 5%), and current non-surgical treatment options are ineffective in treating this disease. A better understanding of disease initiation and progression is necessary, specifically in terms of defining the functional targets of activating KRas mutations, which are found in most cases of pancreatic cancer, and elucidating the role of the inflammatory microenvironment that accompanies disease progression. Thus, this proposal is focused on elucidating novel components of the pathway mediating crosstalk between KRas- expressing tumor cells and their microenvironment.