Aysegul publishes two manuscripts in Nature Communications on metabolic heterogeneity in AML
It has long been known that tumor cells harbor a different energy metabolism compared to normal cells, but underlying molecular mechanisms that dictate such differences are still poorly understood. Studies in the Department of Experimental Hematology (Schuringa lab) have now uncovered the metabolic landscape in acute myeloid leukemia (AML).
Now almost hundred years ago, Otto Warburg observed that tumors can take up high amounts of glucose compared to normal tissue. His studies revealed that, even under aerobic conditions, cancer cells favor anaerobic glycolysis towards lactate production instead of further converting pyruvate to Acetyl-CoA to feed TCA cycle in the mitochondria. This process allows malignant cells to produce ATP more rapidly, produce building blocks, generate a potentially favorable acidic environment to manipulate the immune system and escape from genotoxic effects of ROS. Since then, it has often been proposed that tumor cells adopt a glycolytic phenotype. In AML, this turns out to be both right and wrong. In two recently published papers in Nature Communications we uncover a strong heterogeneity in the metabolic landscape of AML patients. Some patients display a more glycolytic phenotype, while others are mostly driven by mitochondrial oxidative phosphorylation (OXPHOS). Such differences can be instructed by genetics. For instance, we uncover that a subgroup of AML, characterized by FLT3-ITD mutations, express high levels and activity of complex II of the electron transport chain (ETC). In contrast, other AML subtypes that express high levels of the glycolytic gatekeeper PDK1 are much less reliant on OXHOS and secrete high levels of lactate. Even within individual patients, the metabolism of genetically distinct subclones can differ. The identification of signaling networks that instruct these metabolic differences can be targeted, and has opened up new avenues for treatment. However, these metabolic programs are not static entities but can change swiftly as a consequence of extracellular changes or in response to pathway-inhibiting drugs. For instance, while inhibition of ETC complex II enhances apoptosis in FLT3-ITD+ AML, cells also quickly adapt by importing lactate from the extracellular microenvironment. 13C3-labelled lactate metabolic flux analyses reveal that AML cells use lactate as a fuel for mitochondrial respiration. Inhibition of lactate transport by blocking Monocarboxylic Acid Transporter 1 (MCT1) strongly enhances sensitivity to ETC complex II inhibition in vitro as well as in vivo. Our study highlights a metabolic adaptability of cancer cells that can be exploited therapeutically. The papers are published under open access and can be read here (Erdem et al, 2022a) and here (Erdem et al, 2022b).