Metabolic Dependencies in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. Thus, PDA cells must possess biochemical flexibility in order to adapt to austere conditions. A better understanding of the metabolic dependencies required by PDA to survive and thrive within a harsh metabolic milieu could reveal specific metabolic vulnerabilities. These molecular requirements can then be targeted therapeutically, and would likely be associated with a clinically significant therapeutic window since the normal tissue is so well-perfused with an abundant nutrient supply. Recent work has uncovered a number of promising therapeutic targets in the metabolic domain, and clinicians are already translating some of these discoveries to the clinic. In this review, we highlight mitochondria metabolism, non-canonical nutrient acquisition pathways (macropinocytosis and use of pancreatic stellate cell-derived alanine), and redox homeostasis as compelling therapeutic opportunities in the metabolic domain.

Keywords: metabolic dependencies; metabolism; pancreatic cancer; redox homeostasis; targeting metabolism.

Figure 1

Pancreatic ductal adenocarcinoma. (A) Resected human PDA. The arrow identifies the characteristically pale, gray, and hypovascular pancreatic ductal adenocarcinoma. The asterisk marks pancreatic parenchyma. (B) On CT scan imaging with intravenous contrast, PDA appears hypodense (dark gray), while well-perfused normal pancreatic parenchyma shows bright enhancement due to penetration by the contrast.

Figure 2

Metabolic features in PDA cells under nutrient abundance and deprivation. Under nutrient abundance, PDA cells have a proliferative phenotype and macromolecular synthesis is prioritized over ATP generation. Under nutrient deprivation, PDA cells have a survival phenotype, and nutrient conservation with maximal ATP generation are prioritized. OXPHOS, oxidative phosphorylation.

Figure 3

Intrinsic and extrinsic nutrient acquisition pathways in PDA cells. PDA cells hijack stromal elements to fuel the tricarboxylic acid (anaplerosis) and other biochemical processes when nutrients are limited. Carbon is extracted by macropinocytosis (A) and autophagy (B) after auto-digestion by lysosomes. PDA cells also stimulate pancreatic stellate cells to produce and excrete free alanine (C). Non-functional mitochondria are dark in the figure and are targeted for autophagy. Functional mitochondria are colored pink. TCA, tricarboxylic acid.

Figure 4

Signaling pathways that restore redox homeostasis in PDA. Nutrient scarcity in the PDA microenvironment augments oxidative stress. Multiple adaptive strategies are recruited by PDA cells. KRAS signaling promotes NADPH production through glutamine catabolism, followed by ME1 activity. In addition, NRF2 and NADK are upregulated. HuR cytoplasmic translocation stabilizes IDH to enhance reductive power. GLS, glutaminase; GOT, aspartate transaminase; ME1, malic enzyme 1; IDH1, isocitrate dehydrogenase 1; TCA, tricarboxylic acid; ROS, reactive oxygen species; NADK, NAD⁺ kinase.