About Student Research
Emily Smith (2003–2008)
Linking Metabolic Defects and Cancer
After graduating from Saint Peters College in New Jersey, Emily Smith entered Mayo Graduate School in 2002 with an interest in cellular metabolism. She was a perfect fit to fill a pioneering role in a new project in the Maher lab. Unlike other nucleic acids work in the lab, Emily wished to understand the peculiar role of cell metabolism in the origin of human tumors called pheochromocytomas (PHEO) and paragangliomas (PGL). As a Mayo PGL patient, Maher had become intrigued in the unusual genetic inheritance pattern of such tumors. There was an obvious need for a new biochemical perspective with model organisms, and Emily Smith accepted the challenge.
PGL and PHEO tumors run in families. The genetic basis for this predisposition has been traced to defects in a most unusual tumor suppressor gene: succinate dehydrogenase, one of the enzymes of the Krebs cycle of central energy metabolism. Patients that inherit a defective copy of a gene encoding part of the succinate dehydrogenase enzyme are at risk for random loss of the second “good” gene copy. If this happens, the resulting cell loses the function of its Krebs cycle. The expectation would be cell death due to a failure to produce enough energy because of the inability to perform oxidative phosphorylation. Strikingly, this metabolic defect actually appears to induce PGL and PHEO tumorigenesis if it occurs in certain neuroendocrine cells.
How can a central metabolic enzyme be a tumor suppressor? Using the convenience of yeast cell genetics and molecular biology, Emily developed ways to study the impact of loss of succinate dehydrogenase on yeast. In this tumor model, the yeast cells increase levels of reactive oxygen species. Even more interestingly, they accumulate high levels of unused succinate because of the Krebs cycle defect.
Emily’s work underscores unappreciated risks of high intracellular succinate: this metabolic intermediate can poison a family of enzymes that produce succinate as a normal by-product. Among the enzymes at risk for succinate poisoning are key regulatory proteins that modify important transcription factors or the histone proteins of chromatin. While studying yeast, Emily collaborated with the van Deursen lab at Mayo to create the first mouse model of heterozygosity for the SDHB gene encoding a succinate dehydrogenase enzyme subunit. Such mice provide models for human patients at inherited risk for developing familial PGL and PHEO. Emily’s studies of this mouse model set the stage for understanding PGL/PHEO causation, and possible cures or preventions.
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