Autophagy is a cellular catabolic process mediated by a unique intracellular membrane trafficking process and executed by lysosomal degrading activity. It is conserved in all eukaryotic cells and crucial for various physiological events. Deregulation of autophagy has been implicated as a pathogenic factor for multiple human diseases, including cancer. Recent progresses have led to the identification of a central molecular pathway for autophagy, making it possible to understand the mechanism underlying the role of autophagy in cancer progression and to develop autophagy-targeted agents for potential therapeutic purposes. Pancreatic neuroendocrine tumors are the second most common malignancy of the pancreas. The incidence of pancreatic neuroendocrine tumors has continued to rise in recent decades. Most pancreatic neuroendocrine tumors are already metastatic by the time they are diagnosed, and metastatic pancreatic neuroendocrine tumors remain incurable. It is therefore important to get better molecular understanding of pancreatic neuroendocrine tumors progression and to develop new therapeutic agents for combating this devastating disease. Recent evidence, largely based on in vitro cell culture and xenograft studies, suggests that autophagy might be involved in pancreatic tumor development. However, there lacks in vivo studies to address the role of autophagy in pancreatic neuroendocrine cancer. In this proposal, by using an avian virus RCASBP and SV40 large T antigen-based in vivo mouse model for pancreatic neuroendocrine cancer, we will investigate the potential role of autophagy in pancreatic neuroendocrine tumor growth and metastasis. Previously, by using this mouse model, we uncovered that overexpression of Bcl-xL and RHAMMB can stimulate metastasis of primary pancreatic neuroendocrine tumors. Therefore, in this proposal we are able to examine the effect of autophagy on pancreatic neuroendocrine tumor metastasis driven by the two specific molecules: Bcl-xL and RHAMMB. Success of the proposed research will establish the role of autophagy in growth and metastasis of pancreatic neuroendocrine cancer, and provide insights into the potential therapeutic value of autophagy-targeting in preventing outgrowth and metastasis of tumors.
This proposal is to investigate the role of autophagy in the growth and metastasis of pancreatic neuroendocrine tumors, by using in vivo mouse models with defined genetic contexts. This study will lead to better understanding of the molecular pathogenesis of pancreatic neuroendocrine tumors and provide insights into development of novel therapeutic approaches for treating this disease.