Abstract B19: Kras mutation imparts neoplastic potential on duct cells but not acinar cells in a mouse model of obstructive chronic pancreatitis

Abstract

Abstract Understanding the progression of human pancreatic cancer is difficult due to the late stage of diagnosis of this deadly disease. We must therefore rely upon robust model systems to understand how pancreatic cancer arises, how its acute and chronic phases of progression are regulated, and how best to identify and treat it, hopefully still in the early stage. Models of pancreatic ductal adenocarcinoma (PDAC) that accurately reflect human disease are still being developed. To mimic human disease, PDAC must arise from mutations occurring in adult animals and with etiologies relevant to humans. We developed a new mouse model that incorporates obstructive chronic pancreatitis with tissue-specific, adult-onset expression of mutant Kras. We found that KrasG12D expression in duct cells but not in acinar cells led to progression of metaplastic ducts to eventual dysplasia and cancer. In early-stage disease, Kras mutation in acinar cells led to increased acinar-to-ductal metaplasia but did not downregulate p53, thus leading to reduced cell survival. Ducts naturally express much lower p53 levels, however, and there was increased survival of KrasG12D-mediated, duct-derived metaplastic cells. Furthermore, acinar cells upregulated Pdx1 during acinar-to-ductal metaplasia while duct cells did not do so during their metaplastic transition. Without chronic pancreatitis, Kras mutation in acinar cells causes abundant Pancreatic Intraepithelial Neoplasm (PanIN)-like lesions. However, overexpression of Pdx1 in acinar cells in this context permitted acinar-to-ductal metaplasia but prevented PanIN-like lesion formation, suggesting that Pdx1 can repress neoplastic progression. In summary, in the setting of obstructive chronic pancreatitis, ducts are the principal source of cancer development via reduced Pdx1 and p53 levels and increased cell survival. Citation Format: Fong C. Pan, Jessica N. Kim, Chanjuan Shi, Mary K. Washington, Maike Sander, Maureen Gannon, Robert D. Beauchamp, Christopher V. Wright, Anna L. Means.{Authors}. Kras mutation imparts neoplastic potential on duct cells but not acinar cells in a mouse model of obstructive chronic pancreatitis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B19.