The amino acid aspartate is a critical substrate for protein and nucleotide synthesis that must be synthesized intracellularly to support cancer cell proliferation. Aspartate production is metabolically costly, and our work has shown that bolstering aspartate levels in cancer cells in vivo can increase tumor growth rate. These data indicate aspartate is an endogenous metabolic limitation for tumor growth and that any further suppression of aspartate would therefore inhibit cancer growth. Since aspartate levels are dependent on various synthesis pathways and metabolic fates in different conditions, all of which can modified by changes in gene expression and signaling, we will seek to understand how different cancer-relevant biological processes including signaling cascades, metabolic adaptations, and drug sensitivities converge on aspartate metabolism to promote tumor growth and sensitize tumors to therapies.
While metabolism is classically viewed through the lens of efficient ATP production, maximization of biomass synthesis in proliferation requires balancing several other coenzyme systems in addition to ATP. Our work has shown that maintenance of NAD+/NADH by mitochondrial respiration is essential for supporting proliferation, however, there are many other coenzyme systems in cells that are interrelated and are also used to support biosynthesis. Further complication arises when considering that these coenzymes are compartmentalized into organelles which have distinct roles in using these coenzymes to support local and global metabolism. We will determine how modifying coenzyme homeostasis causes network effects throughout metabolism and how these consequences can be exploited to control cell proliferation.
The canonical map of metabolic reactions is often perceived as a complete list of all reactions that occur in all human cells. However, there is no reason to assume that this list is comprehensive in all tissue types and conditions. Work by us and others has identified previously uncharacterized metabolites in a subset of cancer cells, providing a proof of concept that there may be many metabolites yet to be discovered. Using state-of-the-art mass spectrometry and a novel tracing technique we will seek to identify new metabolic products, and potentially entire new metabolic pathways, with the hope of identifying biomarkers and metabolic modifiers of diseases.