An individual requires a balanced set of nutrients in order to maintain physical health and fitness. Metabolism is the process whereby these dietary nutrients are broken down in digestion and are then reformed by the body into the essential building blocks such as fats, sugars and amino acids. Many human diseases are related to disorders in these basic metabolic pathways. For example, cancer cells must become proliferative, requiring both increases in the production of key biosynthetic building blocks and new nutrient acquisition strategies to supply them. Research in my group focuses on understanding at a molecular level the fundamental metabolic processes underlying cellular disease physiology- what pathways and processes contribute to disease and how do cells acquire the nutrients to fuel them? One long-term goal of our research is to characterize the metabolic requirements of cancer cells and tumors in vivo in order to identify and validate new therapeutic targets. Our approach begins with the biochemical, based on integrating new mass spectrometry technology with CRISPR/Cas9 genetic engineering to be able to precisely quantify specific chemicals and thus metabolic fluxes in vivo. By starting with a fundamentals-based perspective on metabolism, we are able to apply our knowledge across different cell types and disease states providing a unifying framework to understand diverse biological phenomena.
Serine, glycine and amino acid metabolism in cancer
It has been long appreciated that certain essential and semi-essential amino acids are required for tumor growth. In fact, administration of the enzyme L-asparaginase, which depletes asparagine in the plasma, is a long-standing component of the treatment for acute lymphoblastic leukemia. Recently, it has been shown that modifying the availability of even non-essential amino acids such as serine and glycine can also alter tumor growth. Glycine may be the simplest amino acid, but it is an essential building block for larger biomolecules such as heme, purines and glutathione. Using isotope tracing and genetic engineering, we have identified glycine consuming pathways that are activated in cancer and characterized their overall contribution to tumor growth. From these studies, it is apparent that the acquisition and transmembrane transport of glycine and other amino acids can be limiting for many cell types. In particular, how cells regulate and acquire glycine remains unknown, despite its critical contribution to antioxidant defense in tumors. We are interested in understanding the quantitative demand for glycine in tumors in vivo and ways to therapeutically modulate glycine availability in both the tumor cell and the environment.
One-carbon and methionine metabolism.
Methionine is an essential amino acid and the functional core for the most important methyl transfer molecule in the body, S-adenosylmethionine (SAM). SAM provides methyl donors for many reactions, including methylation reactions that modify gene expression. Upon the transition from healthy liver tissue to hepatocellular carcinoma, a major metabolic switch occurs between different nutrient sources of one-carbon units for the production of SAM. Our research seeks to ask why thisswitch occurs and if downregulated metabolic pathways might have tumor suppressor-like properties.
Role of folate vitamers in neurodevelopment and cell activation.
Folate metabolism is required for proper fetal development and disruptions to this pathway can result in both gross anatomical abnormalities (microcephaly) as well as disorders of neurodevelopment (seizures). The folate vitamer 5-formyl-THF is not directly required for any biosynthetic process, but deletion of the enzyme (MTHFS) that metabolizes it is embryonic lethal in mice and results in severe multisystem birth defects in humans. 5-formyl-THF is commonly thought of as a storage form of folate and appears to be critical for the initiation of many cellular transformations. Our group is employing mass spectrometry tracing techniques to discover where this folate originates from, how cells mobilize it and what cellular processes in development, immunity and neurology it enables.