Technion Integrated Cancer Centre,
The Ruth and Bruce Rappaport Faculty of Medicine,
Technion - Israel Institute of Technology
Last century, Otto Warburg observed that cancer tissues have high rates of glycolysis in the presence of oxygen. This was attributed to defects in mitochondrial respiration, and is now considered a key hallmark of cancer. Nevertheless, convincing evidence that mitochondrial dysfunction causes metabolic switch and tumorigenesis are scarce. Recently, the identification of mutations in key metabolic enzymes with a causal link to tumorigenesis awakened interest in Warburg's hypothesis. Cancer-associated mutations have been identified in genes coding for tricarboxylic acid (TCA) cycle and closely related enzymes. Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are TCA cycle enzymes while SDH is also complex II of the mitochondrial respiratory chain. Despite their key housekeeping activities, the genetic loss of FH or of any of the SDH subunits is associated with susceptibility to cancers. SDH or FH inactivation leads to the accumulation of succinate or fumarate, respectively. This in turn causes the activation of hypoxia-inducible factors and the inhibition of α-ketoglutarate-dependent histone and DNA demethylases, establishing pseudohypoxic and hypermethylator phenotypes. These biochemical changes are associated with hyper-vascularization and epithelial to mesenchymal transition (EMT) resulting in increased invasiveness and motility of these tumors. However, not much is known about the metabolic mechanisms which enable the survival and proliferation of SDH- or FH-defective cells. We generated genetically engineered mouse models in which FH or SDH activity has been ablated and identified metabolic pathways dispensable in normal, but essential in TCA cycle truncated cells. Our study provides mechanistic understanding of the onco-metabolic role of the TCA cycle intermediates fumarate and succinate, and it suggests novel therapeutic approaches for treating these metabolically-atypical neoplasms.