Abstract 1837: High Ras activity promotes neoplasia in pancreatic ductal cells

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy and is the third leading cause of cancer-related deaths in the United States. Next generation sequencing efforts have revealed KRAS mutations occur in over 99% of pancreatic ductal adenocarcinomas and are thought to be the initiating mutation for pancreatic cancer. Despite the high prevalence of KRAS mutations in pancreatic cancer patients, murine models expressing endogenous levels of mutant Kras in pancreatic cells do not develop PDAC. A number of publications have revealed that acinar cells are more sensitive to early neoplastic lesion formation in the presence of Kras mutations than ductal cells. In these models, a second genetic hit (loss of tumor suppressor TP53, SMAD4 or CDKN) is required for the development of invasive PDAC, including transforming pancreatic ductal cells. Recent data has revealed a novel role for high levels of Ras activity in acinar cells in the tranformation of this cell type to PDAC (Ji, B., 2009). We hypothesized based on other preliminary data that high levels of Ras activity would transform ductal cells. To test this hypothesis, we studied the role of constitutively active high levels of Kras activity in acinar and ductal cells by expressing an inducible KrasG12V allele in Ptf1a:CreERT2 (acinar cell specific) and Hnf1b:CreERT2 (ductal cell specific) mice. Similar to previously published work, high levels of Ras activity in acinar cells resulted in PDAC and a remarkably low survival time of 10 days after mice were injected with tamoxifen. Mice with elevated Ras activity in ductal cells needed to be euthanized two weeks after tamoxifen injection and manifested a cancer cachexic phenotype. Histological analysis of these mice revealed high grade oncocytic intraductal neoplasia and the phenotype extended throughout the pancreatobiliary ducts. Western blot analysis of human PDAC and Cholangiocarcinoma tissue revealed similar levels of Ras activity to our murine models, confirming human equivalent high Ras expression to both animal models. Oncocytic tumors are characterized by an abundance of mitochondria. Thus, we are currently studying metabolic alterations and mitochondria accumulation in ductal and acinar cells expressing high Ras activity. Our goal is to determine how mitochondrial alterations play a role in progression or inhibition of tumors in ductal vs acinar cells. Citation Format: Kanchan Singh, Melissa A. Pruski, Wasim A. Dar, Kishore Polireddy, John S. Bynon, Mamoun Younes, Anirban Maitra, Craig D. Logsdon, Jennifer M. Bailey. High Ras activity promotes neoplasia in pancreatic ductal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1837. doi:10.1158/1538-7445.AM2017-1837