The Pancreatic Tumor Microenvironment Buffers Redox Imbalance Imposed by Disrupted Mitochondrial Metabolism

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and consequently nutrient and oxygen access and drug delivery. Concurrently, recent work also demonstrates that the TME directly provides metabolites that facilitate cancer cell survival, growth, and therapeutic resistance. Redox imbalance is another restraint on cellular proliferation, yet it is unknow how the TME contributes to the maintenance redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle (MAS), disturbs redox homeostasis and halts proliferation of PDA cells in vitro. Surprisingly, we found GOT2 knockdown has no effect on in vivo tumor growth. We demonstrate that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts (CAF). More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Blocking pyruvate uptake through genetic or pharmacologic inhibition of monocarboxylate transporter 1 (MCT1) abrogated pyruvate-mediated restoration of redox homeostasis. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.