Metabolic Adaptations of Pancreatic Cancer to a Nutrient-Deprived Environment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common types of the pancreatic cancer, and it is notoriously deadly because the tumor usually is not diagnosed until it’s advanced. Several metabolic rewiring mechanisms have been revealed as a hallmark of pancreatic cancer due to its flexibility to acquire nutrient sources through pathways like autophagy and macropinocytosis from the microenvironment. PDAC resides in a unique environment where the tumors are largely occupied by the dense stroma and other types of cell types, which might result in limited nutrient availability. To understand how PDAC cells manage to overcome limited-glucose and -glutamine conditions, I derived cells that can adapt and proliferate under a prolonged low glucose-low glutamine (L-L) media (these cells are described as adapted cells), and found that they are more tumorigenic in vivo. Mechanistically, I demonstrated that the adapted cells can synthesize glutamine from other amino acids sources, such as leucine or glutamate with elevation in glutamine synthetase (GS) protein expression. In addition, adapted cells maintain the activity of mechanistic target of rapamycin complex 1 (mTORC1) under the L-L conditions. Apart from some of the well-known regulations underneath mTORC1 signaling, I demonstrated that mTORC1 activity can also stabilize GS protein, which might further reinforce the glutamine synthesis ability of adapted cells. To better understand if glutamine synthesis is present in vivo and in patients, I showed that PDAC can synthesize glutamine in an ex vivo setting by 15N-tracer, and GS protein is expressed in various degrees in PDAC patients. In addition, genetic and pharmacological approaches to inhibit GS suppressed cell proliferation under nutrient-poor conditions. These results highlight the possibility that GS can be a potential therapeutic target in PDAC.