Metabolic reprogramming in pancreatic cancer
Pancreatic ductal adenocarcinomas (PDA) must contend with particularly severe metabolic stress as the hypovascular, fibrotic tumor microenvironment results in extreme hypoxia and limited nutrient availability. In turn, a number of acquired alterations in nutrient acquisition and utilization are required for pancreatic growth and survival. These include increasing glucose uptake, scavenging of serum lipids and proteins from the extracellular space, and activation of autophagy, a process of recycling cellular components through engulfment in modified membranes and degradation in lysosomes. Many of these adaptive changes in metabolism may represent important nodes that could be targeted for therapeutic intervention. Recent work from our laboratory has sought to uncover the molecular programs underlying metabolic reprogramming in PDA. We have defined an aberrantly activated transcriptional network driving increased function of the autophagy-lysosome system that is required to maintain energy homeostasis in PDA. Additional projects focus on deciphering the impact of mutations in key PDA genes on metabolic circuitry of tumor cells, and studying regulation of tumor metabolism as barrier for progression of benign precursors to malignant cancer.