Discovery of New Metabolic Pathways and Liabilities in Cancer Cells
Cancer cells use reprogrammed metabolic pathways to grow and resist stress encountered in the tumor microenvironment. We believe that reprogrammed pathways facilitate malignant transformation and enable tumor progression. Identifying these pathways will allow us to better understand the biology of cancer and to uncover new therapeutic targets. Our lab uses metabolomics, metabolic flux analysis, cell biology and animal models of cancer to study how tumor cells generate energy, build macromolecules and maintain redox balance. We seek to identify the processes, both intrinsic and extrinsic to the cancer cell, that affect tumor metabolism and to discover context-specific metabolic vulnerabilities that might provide a basis for new treatments.
Our lab has found a metabolic pathway that prevents oxidative stress in anchorage-independent cells (see figure). We discovered that loss of anchorage enhances mitochondrial reactive oxygen species (ROS), which limit cell survival and growth. Cancer cells counteract mitochondrial ROS by inducing a metabolic pathway that transmits reducing equivalents as NADPH from the cytosol to the mitochondria. This pathway involves cytosolic reductive carboxylation of alpha-ketoglutarate (alpha-KG) by isocitrate dehydrogenase-1 (IDH1) using NADPH produced by the pentose phosphate pathway. The resulting isocitrate or citrate enters the mitochondria, and IDH2 decarboxylates it, which generates mitochondrial NADPH to mitigate ROS (Jiang et al., Nature 2016).