Defining the Contributions of Pancreatic Ductal and Acinar Cells to Tumorigenesis

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DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth-leading cause of cancer deaths in the United States. The 5% five-year survival rate demonstrates the need for improved treatments. To address that need, a better understanding of the mechanisms of pancreatic carcinogenesis is needed. Several factors that may determine tumor phenotype include: 1) cell type of tumor origin, 2) aggregate genetic mutations acquired by transformed cells, and 3) sequence by which genetic mutations are acquired. Based on previous studies and our preliminary data, my hypothesis is that cellular origin is an important factor in determining pancreatic tumor phenotype. Although pancreatic ductal adenocarcinoma (PDA) is the most common form of pancreatic cancer, we still do not know which cell type gives rise to it. This lack of insight is also true for other types of pancreatic tumors. My objectives are to study the tumorigenic effects of mutations expressed specifically to adult pancreatic acinar cells (AC) or ductal cells (DC). I will use two mouse models. The first reproduces PDA via concurrent mutations in k-ras and Trp53; the second is a novel model for solid pseudopapillary tumor (SPT) that our laboratory recently developed and is based on exogenously activated ¿-catenin via Cre recombination-excision of exon 3 (¿-catex3). My first aim is to target mutations to only AC in adult mice. I will cross mice carrying conditionally expressed alleles of mutated k-ras and Trp53 (k-rasG12D/Trp53R172H) or ¿-catenin (¿-catex3) to mice carrying tamoxifen-activated Cre that are expressed to AC via a promoter derived from the elastase gene. Tumors will be characterized with histology and immunohistochemistry. Gene expression profiles will be analyzed by quantitative PCR. My second aim is to evaluate the effects of k-rasG12D/Trp53R172H or ¿-catex3 in DC. Currently, there is no promoter to direct Cre to only ductal epithelium. Instead, I will isolate and culture DC from adult krasG12D/Trp53R172H or ¿-catex3 mice and activate them in vitro with lentiviral delivered Cre. Luciferase will be concurrently introduced to allow in vivo monitoring of tumor growth via luminescence. We will re-implant these cells into nude mice and characterize formed tumors in the same manner as in Aim 1. PUBLIC HEALTH RELEVANCE: Identifying the types of cells that give rise to pancreatic tumors has several important implications. First, we will be able to focus additional research efforts towards that particular cell type and pursue more detailed studies into the mechanisms behind pancreatic tumorigenesis. Secondly, we may be able to deliver more targeted therapy that has increased efficacy and reduced side effects.