Harnessing metabolic dependencies in pancreatic cancers

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a 5-year survival rate of <10%. The tumour microenvironment (TME) of PDAC is characterized by excessive fibrosis and deposition of extracellular matrix, termed desmoplasia. This unique TME leads to high interstitial pressure, vascular collapse and low nutrient and oxygen diffusion. Together, these factors contribute to the unique biology and therapeutic resistance of this deadly tumour. To thrive in this hostile environment, PDAC cells adapt by using non-canonical metabolic pathways and rely on metabolic scavenging pathways such as autophagy and macropinocytosis. Here, we review the metabolic pathways that PDAC use to support their growth in the setting of an austere TME. Understanding how PDAC tumours rewire their metabolism and use scavenging pathways under environmental stressors might enable the identification of novel therapeutic approaches.

Figure 1.. Metabolic alterations in pancreatic cancers.

(A) In pancreatic cancer cells, oncogenic KRAS^G12D upregulates the uptake of glucose and enhances glycolysis. Additionally, glycolytic intermediates are shunted into the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway. Ultimately, this metabolic rewiring produces metabolites required for the synthesis of DNA and/or RNA and substrates for glycosylation. (B) In pancreatic cancers, the non-essential amino acid glutamine is metabolized by a non-canonical pathway, whereby glutamine-derived glutamate is converted into aspartate. Aspartate is transported into the cytosol where it undergoes a series of metabolic reactions that ultimately lead to increased NADPH production contributing to redox balance. Abbreviations: HK, Hexokinase; GFAT, Glucosamine—fructose-6-phosphate aminotransferase isomerizing; GlcNAc, Uridine diphosphate N-acetylglucosamine; Gln, Glutamine; Glu, Glutamate; Ala, Alanine; Asp, Aspartate; Cit, Citrate; Suc, Succinate; Fum, Fumarate; Mal, Malate; OAA, Oxaloacetic acid.

Figure 2.. Pancreatic cancers rely on autophagy and lysosomal scavenging.

(A)The molecular mechanism of autophagy can be categorized by four main stages: initiation and/or elongation, closure, fusion with the lysosome, and degradation. Nutrient starvation is a major trigger for autophagy activation through mTOR and AMPK. A series of protein–lipid interactions convert pro-LC3B into LC3B-I by ATG4B. LC3B is subsequently conjugated into phosphatidylethanolamine (PE), producing LC3B-II, via ubiquitin conjugation-like E1-E2-E3 series enzymes ATG7, ATG3, and ATG12-ATG5-ATG16L1 respectively. LC3B-II is associated with the autophagosome and acts as a docking site for autophagy cargo receptors. Cargo, such as damaged proteins or organelles are sequestered in a double membrane vesicle called an autophagosome. Ultimately, the autophagosome fuses with the lysosome, and the content is degraded. Degraded products are shuttled back into the cytoplasm where they can be used in various metabolic pathways. Autophagy and lysosomal degradation can be inhibited by compounds such as hydroxychloroquine, Lys05, and bafilomycin (BAFA1). Other compound tools targeting other modulators of autophagy such as ATG4B inhibitors are currently being tested. (B) Macropinocytosis, a non-selective endocytic pathway, allows extracellular content, such as albumin, to be degraded by the lysosome and can provide amino acids and other metabolites to the cell. Macropinocytosis can be inhibited by EIPA (5-(N-ethyl-N-isopropyl)-Amiloride).