BLOOMINGTON, Ind.—One of the most well-known hallmarks of cancer is the rapid, uncontrollable growth of cancer cells, which leads to tumors and metastasis. Recently, a team at Indiana University found a new way to study a molecule that plays a role in the growth of some cancers and neurodegenerative disorders—and in the rapid growth of fruit flies. The study, “Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth,” was published in the Proceedings of the National Academy of Sciences. The work was supported in part by the National Institute of General Medical Sciences of the National Institutes of Health, the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.
The molecule in question is L-2-hydroxyglutarate, or L-2HG, which is commonly regarded as an "oncometabolite," a molecule that can promote tumor formation and growth. L-2HG has been seen in tumor cells from patients with kidney and brain cancers (specifically gliomas and renal cell carcinomas), and in patients with L-2-hydroxyglutaric aciduria, a rare neurological disorder characterized by muscle weakness, seizures and damage to the parts of the brain responsible for muscle movement, speech, vision, emotion and memory. This study is the first one to show how L-2HG acts in a living system without cancer.
"We found that the same molecule implicated in human cancers is also produced by fruit flies during their larval stage," said senior author Jason M. Tennessen, an assistant professor in the IU Bloomington College of Arts and Sciences' Department of Biology. "The discovery is significant because it provides the first animal model to understand how these molecules function in healthy cells. If we can determine the function of this molecule in normal cells, we can better understand how it causes human disease."
"How the function of L-2GH differs between healthy and diseased tissues is poorly understood," Tennessen added. "In addition to establishing a new model for studying this cancer-related molecule, our study demonstrates that a compound previously regarded as a metabolic waste product actually functions in healthy animals."
As noted in the study, L-2GH “was recently discovered to control immune cell fate, thereby demonstrating that it has endogenous functions in healthy animal cells. Here, we find that the fruit fly, Drosophila melanogaster, also synthesizes high concentrations of L-2HG during normal larval growth … L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification and cell differentiation. “
Tennessen's lab made this discovery while working to develop fruit flies lacking dehydrogenase, an enzyme believed to fuel tumor growth. When they analyzed normal and mutant flies using metabolomics, the research team found the mutant flies stopped producing lactate and L-2HG.
Upon further analysis of the normal flies, Tennessen and his team discovered that flies usually produce L-2HG at high levels during their larval stage, in which they grow over 200 times in size over the course of several days. In addition, they found a mechanism that enables the flies to control the accumulation of L-2HG—an important factor, since these high levels of L-2HG are carefully controlled. If the precise factor by which this mechanism detects L-2HG levels and cuts off production when a sufficient amount is accumulated, it could potentially offer a new avenue for cancer research, should L-2HG levels prove to be similarly controllable in humans.
The next step, according to Tennessen, is to investigate precisely how L-2HG functions in healthy animals. "What happens if there's too much of it, or too little? Does it accelerate growth, or slow it down? Exactly what genes does it control? There’s a lot of important questions we can answer using the power of fly genetics," he concluded.
SOURCE: IU press release
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