Metabolic Adaptations to Hypoxia
Solid tumors frequently outgrow their blood supply and reside in nutrient- and oxygen-poor environments. As oxygen is essential for at least 145 metabolic reactions, a decrease in oxygen levels (hypoxia) impacts the efficiency of metabolic pathways such as mitochondrial oxidative phosphorylation, lipid unsaturation or cholesterol biosynthesis. Furthermore, during hypoxia cancer cells are exposed to oxidative stress – as there is a higher probability for oxygen molecules to generate ROS due to their partial reduction. While it is clear that cancer cells rewire their metabolism to sustain proliferation under oxygen deprivation, the pathways enabling cell growth and survival are not completely understood.
We have previously identified that low oxygen triggers a dramatic decrease in the levels of aspartate, an essential precursor of nucleotide and protein synthesis that becomes limiting for hypoxic cancer cells (Garcia-Bermudez et al. Nat Cell Bio, 2018). By using functional genomics and metabolomic analyses, our lab will systematically identify other limitations of hypoxic tumors and develop therapeutic strategies against them.