Abstract 5222: Repression of neuronal genes protects the pancreas from certain injuries and aberrant plasticity

Abstract

Abstract Among the major cancer types, pancreatic ductal adenocarcinoma has one of the lowest survival rates with little improvement over the past 3 decades. To address this dire clinical need, this study explores the unique and underexploited neuronal property of the pancreas that correlates with greater injury and pancreatic cancer development. The pancreas has a remarkable innate plasticity, and a shift toward neuroendocrine transdifferentiation has been shown to correlate with poor survival and tumor progression in numerous cancers, such as lung and prostate cancers. Recent reports show a subpopulation of cells within pancreatic tumors that express neuroendocrine-related genes correlate with poor outcome and chemoresistance. We hypothesize one regulator of this ductal-neuroendocrine lineage plasticity may be REST, a transcriptional repressor most known for orchestrating neuronal development. Tissue microarray of human pancreatic cancer shows patients negative for REST had a lower overall survival than patients positive for REST. To investigate the role of REST in the pancreas, we developed a novel transgenic mouse model with REST conditionally knocked out of the pancreas. REST KO resulted in an increase of neuroendocrine markers and an increase of zymogen granules, resulting in a lighter, cloudy appearance of the pancreas. When pancreatic injury was introduced by injections of cholecystokinin analog caerulein to induce acute pancreatitis, the REST KO mice show greater serum amylase levels and higher pancreatic edema indicating greater pancreatitis. Furthermore, an increase in neuronal-related genes was observed within REST KO pancreas relative to control. We then investigated the role of REST during cancer-promoting injuries such as chronic pancreatitis. Mice were administered a 10-week series of caerulein injections, and histology was evaluated. As expected, REST KO mice experienced greater inflammation, injury, and pre-neoplastic lesions. Further directions include investigating REST KO during later stages of pancreatic cancer injury by crossing REST KO mice with mutant KRAS mice, as oncogenic KRAS is a leading driver of pancreatic cancer. We expect REST KO to increase neuroendocrine properties that will accelerate KRAS-induced pancreatic cancer development. In conclusion, we hypothesize that loss of REST increases neuroendocrine-like properties of the pancreas that leads to a greater injury, suggesting that REST plays a protective effect against pancreatic damage and pancreatic cancer development. Furthermore, our novel REST KO mice may prove to be a useful model to investigate how neuroendocrine properties may promote pancreatic cancer development and drug resistance. Understanding neuronal influences during pancreatic cancer development could have multiple implications for cancer patients and warrants further investigation. Citation Format: Julie K. Bray, Ola Elgamal, Lais Da Silva, Dhruvit Sutaria, Xiuli Liu, Kristianna Fredenburg, Thomas D. Schmittgen. Repression of neuronal genes protects the pancreas from certain injuries and aberrant plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5222.