About Student Research
John A. Smestad (2015-2019)
How do "oncometabolites" cause cancer?
A native of Rochester, Minnesota, John A. Smestad received his undergraduate degree in chemistry from Wheaton College near Chicago, and worked as a research scientist for two years before gaining admission to the Medical Scientist Training Program (MSTP) M.D.-Ph.D. program at Mayo Clinic.
In the Maher Lab, John is applying his fascination with clinically relevant biochemistry and genomics to understand the molecular basis of familial paraganglioma (PGL), a rare cancer that runs in families. PGL occurs when neuroendocrine cells grow out of control. Surprisingly, the inherited mutations that cause risk of PGL in families lead to mistakes in the structure of a metabolic enzyme called succinate dehydrogenase. This enzyme plays a key role in allowing cells to convert sugar into energy. Why breaking such an enzyme contributes to cancer is the puzzle, and John is working to assemble a few more of the pieces.
John is studying the hypothesis that the broken succinate dehydrogenase enzymes in PGL cancer cells cause unprocessed succinate to accumulate. The unprocessed succinate has the ability to poison other enzymes, some of which then fail to properly regulate genes. Because of too much succinate, a normal cell chemical (metabolite) is thought to cause cancer when it accumulates in such cells — creating what is called an "oncometabolite." John is interested in understanding how succinate poisoning affects expression of all genes in affected cells, how oxygen and other nutrients affect this process, and whether nontoxic approaches might be envisioned to reverse these effects. Such approaches might first be tested in cells and animals for eventual applicability in PGL patients.