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.

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

“…Specifically, pancreatic cancer is a disease that could greatly benefit from mitochondrial metabolism targeting [1][2][3][4][5]. The most frequent pancreatic cancer is Pancreatic Ductal AdenoCarcinoma (PDAC), the fifth leading cause of cancer death in the United States by 2017 [6] and the 13th worldwide by 2018 [7].…”

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

“…This suggests DNAJA1 skews BxPC-3 towards alanine production while MIA PaCa-2 is directed to lactate. Investigations into PDAC cellular communication has shown that stellate cells provide alanine to pancreatic cancer cells in order to promote tumor progression and metastasis (20). This increase in alanine in D1-Bx supports increased cellular invasion and survival, which is discussed further in the following sections.…”

“…In these D1 cells, we observed significant dysregulation in fundamental metabolic pathways, marginal loss of mitochondrial dispersion, and loss of lysosomal integrity, which collectively impacted cellular survival. DNAJA1 overexpression exhibits a distinct impact on tumor specific metabolic processes like aerobic glycolysis and glutaminolysis, which is coupled with a response specific to the two phenotypically unique pancreatic cancer cells (8,19,20).…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…Nutrient provision by altered metabolic pathways is another important aPSC contribution to PaCa cell progression. This proceeds through increased glycolysis, amino acid (AA) production from protein degradation, by glycosylation and fatty acid synthesis, called the metabolic switch (507). Accordingly, glycolytic enzymes such as hexokinase-2, enolase-2, LDHA, and B 1 (508) and glycolytic metabolites are elevated (509).…”