Abstract 1336: Autophagy inhibition reverses EMT and reduces 3D growth of pancreatic adenocarcinoma cells in vitro and in vivo

Abstract

Abstract Pancreatic cancer is the 4th most fatal cancer in US men and women, with 5-year survival rates under 5%. Obesity is one risk factor known to increase pancreatic cancer risk by facilitating tumorigenesis and metabolic processes associated with pancreatic tumor growth and progression. Autophagy is the catabolic process of recycling cellular organelles to provide energy to the cell and is often induced when cells become stressed. Autophagy plays a critical role in cancer growth and metastasis, and in many cancers autophagy inhibition decreases the size of tumors in in vivo models. Our current studies investigate the link between the autophagy inhibition and the invasiveness of pancreatic cancer. To understand the role of autophagy on invasion, EMT and 3D growth in pancreatic cancer, Kras-driven Panc02 mouse pancreatic cancer cells were transduced using CRISPR/Cas9 to cleave the gene encoding autophagy related protein 5 (Atg5). Atg5 deletion resulted in striking morphological alterations, including a more epithelial-like appearance. In addition, Atg5 deletion resulted in increased expression of the epithelial marker E-Cadherin, concurrent with decreased expression of mesenchymal markers N-Cadherin and Snail. Furthermore, Atg5 deletion resulted in significant decreased invasiveness and ability to form colonies under anchorage-independent conditions, with no significant difference in 2D cell growth. Orthotopic, intrapancreatic injection of these cells into C57BL/6 mice resulted in reduced tumor take and growth. Taken together, these results for the first time show that autophagy inhibition results in reduced EMT and 3D growth in pancreatic adenocarcinoma and highlight autophagy's role in pancreatic adenocarcinoma progression. Citation Format: Jane B. Pearce, Ciara H. O'Flanagan, Stephen D. Hursting. Autophagy inhibition reverses EMT and reduces 3D growth of pancreatic adenocarcinoma cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1336.