Targeting cancer cell metabolism in pancreatic adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.

Keywords: glutamine; glycolysis; hypoxia; metformin; warburg effect.

Figure 1. Overview of PDAC cell metabolism in response to microenvironment constraints and oncogenic signals

A. The Warburg effect sustains metabolic needs of PDAC proliferative cells; B. The PKM2 tyrosine kinase enhances transcriptional activity of several factors such as hypoxia-inducible factor HIF1-α, inducing the Warburg effect through a positive feedback loop; C. the hexosamine biosynthetic pathway uses glucose and glutamine influx for protein O-GlcNAc glycosylation and its inhibition induces an unfolded-protein response-dependent cell death; D. PDAC-specific glutamine metabolism: glutamine-derived aspartate is converted into oxaloacetate, then into malate, and finally into pyruvate, resulting in an increased NADPH/NADP+ ratio that provides the reducing power to maintain reduced glutathione pools; E. glutamine is a nitrogen donor for amino acid and nucleotide biosynthesis; F. ASNase may be a promising therapy since a majority of PDAC express no or low ASNS; G. macropinocytosis and autophagy support the metabolic needs of PDAC cells; H. PDAC overexpresses enzymes involved in fatty acid synthesis. Glc : glucose; Gln: glutamine; Glu : glutamate; Asn : asparagine; ASNase : asparaginase; ASNS : asparagine synthetase; GSH : glutathion; LDH-A : lactate dehydrogenase-A; ME : malic enzyme; NADP : nicotinamide adenine dinucleotide phosphate; OXPHOS : oxidative phosphorylation; PKM : pyruvate kinase muscle-isozyme.