Metabolism in Pancreatic Cancer

Abstract

Despite knowledge of an increasing number of genetic changes present in pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, it remains one of the cancers with the poorest prognosis, and the development of novel therapies that target its unusual biology and metabolic features is imminently required. Pancreatic tumor cells are thought to evolve under the conditions of limited oxygen and nutrient supply due to high levels of stromally produced extracellular matrix and associated poor blood supply. The prevalence of oncogenic KRAS mutations in PDAC, together with inactivation of TP53, CDKN2A, and SMAD4, predicates the engagement of distinct adaptive metabolic features that maximize the uptake and utilization of limiting oxygen and nutrients. Rewiring of the metabolism of glucose, amino acids, and lipids provides biosynthetic/metabolic intermediates required to maintain proliferation and survival, while the induction of autophagy and macropinocytosis permits repurposing of nutrients by PDAC tumor cells. Finally, PDAC tumor cells affect their neighboring cells, activating pancreatic stellate cells to produce a dense fibrotic stroma and provide nutrients in a paracrine manner, while inhibiting an effective antitumor immune response by restriction of nutrients from immune effector cells. It is hoped that by targeting such aberrant metabolism and nutrient utilization additional therapeutic options might soon be available in PDAC.