Isaac Marin-Valencia, MD, publishes metabolic features in brain tumors that could lead to new therapeutic approaches
By Julie Kirchem, Department of Neurology and Neurotherapeutics
First, his research won a grand prize at UT Southwestern’s Postdoctoral Research Symposium in 2011. Now, his investigation of the Warburg effect in vivo has led to a publication in the journal Cell Metabolism.
Isaac Marin-Valencia, MD, along with a group of experts in metabolism and neuro-oncology at UT Southwestern, challenged a 50-year-old hypothesis by Nobel Prize winner Otto Warburg. He explained his research findings and their significance to future therapies in a recent interview.
Q. What did you discover?
A. In vitro, cancer cells preferentially metabolize glucose to lactate, despite sufficient levels of oxygen to support glucose oxidation in the mitochondria, the so-called "Warburg effect". However, little is known about the fate of glucose and other nutrients in tumors growing in their native microenvironment. In this work, we performed primarily a metabolic analysis of 13C-glucose in human orthotopic tumor models (HOTs), in which cells isolated from human glioblastomas (GBM) were implanted directly into the mouse brain. GBM displayed glycolysis, as expected for aggressive tumors, but also manifested unexpected metabolic complexity, that is, the oxidation of glucose through the citric acid cycle (CAC) and the use of glucose to supply anaplerosis and other biosynthetic pathways. Prominent metabolic differences were observed between tumors and surrounding brains, notably the accumulation of a large glutamine pool within the tumors. These results indicate that in vivo, GBM cells utilize mitochondrial glucose oxidation to support aggressive tumor growth.
Q. What is the significance of your finding to the future of research?
A. With this work we now have a better understanding of the key biochemical pathways that support energetics for tumor growth and proliferation. This does indeed have implications for targeting therapies to some of these pathways, for example, pyruvate dehydrogenase or CAC. In addition, this study provides a tractable approach to metabolic dissection in representative tumor mouse models.
Q. How were you able to disprove a research finding that has been accepted by the scientific community for more than 50 years?
A. We initially hypothesized that the Warburg effect is not exclusive of oxidation in vivo, and does not arise from failure to flux through pyruvate dehydrogenase, the enzyme that links glycolysis and the CAC. We used 13C nuclear magnetic resonance (NMR) spectroscopy to test this hypothesis by analyzing the fate of 13C-glucose in the tumor. The fact that derivatives of CAC intermediates (i.e., glutamate and glutamine) are labeled with 13C proves that 13C-glucose is oxidized in the CAC in vivo, indicating that tumor cells utilize mitochondrial glucose oxidation to support growth in their native environment.
Q. Could this lead to new treatments?
A. Understanding the mechanisms of tumor metabolism facilitates the generation of targeting therapies to block or to slow down fundamental pathways (i.e., pyruvate dehydrogenase pathway), which in turn may halt tumor cell growth and proliferation.
Q. What is the next step for your research?
A. To dissect other relevant biochemical pathways and alternative nutrients involved in brain tumor metabolism.
Marin-Valencia will continue his training in the pediatric neurology residency program (research track) at UT Southwestern. His research will focus on neurometabolism and neurocognitive disorders.