Pancreatic cancer remains a deadly disease, with a 5-year survival rate of 12%. Pancreatic cancers are noted for complex tumour microenvironment, low vascularity, and metabolic aberrations. Hypoxia and nutrient deprivation in pancreatic tumors and their surrounding microenvironment are well-established to underlie therapy resistance. Efforts to better understand the metabolic adaptations driving pancreatic cancer progression will identify vulnerabilities that could be therapeutically targeted to improve patient survival. AMP-activating protein kinase (AMPK) is a master regulator of cellular and organismal metabolism that acts as a sensor of cellular energy by altering metabolism when energy levels are low. AMPK signaling has been demonstrated in multiple tumor contexts to provide cancer cells with the flexibility to adapt to metabolic stresses, such as nutrient and oxygen deprivation. Given that AMPK plays a key role in the response to nutrient deprivation, we are interested in understanding the impact of AMPK on pancreatic cancer initiation and progression. Using orthotopic and genetically-engineered mouse models of pancreatic cancer, we have found that AMPK has tumor suppressive functions in pancreatic cancer. Here, we report the effects of deleting AMPK in a retrograde intraductal lentiviral model of pancreatic ductal adenocarcinoma, in which KrasG12D, Trp53fl/fl, AMPKa1fl/fl, and AMPKa2fl/fl are induced specifically in the pancreas leads to decreased overall survival. In parallel, we observed that orthotopically implanted AMPK-depleted pancreatic cancer cells developed larger tumors than their control counterparts. We plan to investigate the tumor suppressive function of AMPK in order to aid in our understanding of the metabolic stresses tumors face and how they may trigger adaptive changes in cancer cells.