The complex landscape of pancreatic cancer metabolism

Abstract

Pancreatic ductal adenocarcinomas (PDA) are extremely aggressive cancers and currently available therapies are only minimally effective in treating this disease. Tackling this devastating cancer has been a major challenge to the scientific and medical communities, in part due to its intense therapeutic resistance. One of the aspects of this tumor that contributes to its aggressive behavior is its altered cellular metabolism. Indeed, PDA cells seem to possess the ability to adapt their metabolism to the particular environment to which they are exposed, including utilizing diverse fuel sources depending on their availability. Moreover, PDA tumors are efficient at recycling various metabolic substrates through activation of different salvage pathways such as autophagy and macropinocytosis. Together, these diverse metabolic adaptations allow PDA cells to survive and thrive in harsh environments that may lack nutrients and oxygen. Not surprisingly, given its central role in the pathogenesis of this tumor, oncogenic Kras plays a critical role in much of the metabolic reprogramming seen in PDA. In this review, we discuss the metabolic landscape of PDA tumors, including the molecular underpinnings of the key regulatory nodes, and describe how such pathways can be exploited for future diagnostic and therapeutic approaches.

Fig. 1.

A typical PDA cell is depicted showing schematics of representative metabolic pathways that are altered in the disease in response to oncogenic Kras. Enzymes whose expression is increased by Kras are indicated with an asterisk. Increased glucose uptake fuels glycolysis (leading to increased lactate production), anabolic pathways such as the non-oxidative arm of the PPP (producing ribose for nucleotide biosynthesis) and the HBP (producing precursors for glycosylation). Glutamine is a key metabolite that is utilized to fuel the TCA cycle and maintains redox homeostasis in PDA through a novel pathway (shown in orange) that leads to NADPH production. PDA are efficient metabolic scavengers and use autophagy (intracellular) and macropinocytosis (extracellular) to provide metabolic substrates through cargo degradation via the lysosome. Lipids are also taken up extracellularly to provide fatty acids. HK1/2, hexokinase 1 and 2; PFK1, phosphofructokinase 1; ME1, malic enzyme; GOT1/GOT2, aspartate aminotransferase 1 and 2; MDH1, malate dehydrogenase; GLS, glutaminase; GFPT1, glutamine fructose-6-phosphate amidotransferase; RPIA, ribose 5-phosphate isomerase A; RPE, ribulose-5-phosphate-3-epimerase; Asp, aspartate; OAA, oxaloacetate; G6P, glucose 6-phosphate; Ru5P, ribulose 5-phosphate; R5P, ribose 5-phosphate; X5P, xylulose 5-phosphate. LDH, lactate dehydrogenase; αKG, alpha keto-glutarate; GlcN6P, glucosamine-6-phosphate; UPD-GlcNAc, uridine diphosphate N-acetylglucosamine; MCT, onocarboxylate transporter; GLUT, glucose transporter.