Growing pains
March 2017
by Rachel Flehinger  |  Email the author

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BLOOMINGTON, Ind.—Scientists at Indiana University Bloomington have discovered that a molecule present in the larval stage of fruit flies is the same as one implicated in human cancers. The research shows that the extreme growth experienced by fruit flies in their earliest stage of life is biochemically related to cancer cell growth, thus opening a new avenue for cancer research.
 
“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.”
 
The IU researchers were the first to discover that fruit flies produce L-2-hydroxyglutarate, or L-2HG, commonly known as an “oncometabolite” and known to promote tumor formation and growth. Their discovery was a fortunate by-product of research into the enzyme lactate dehydrogenase, thought to fuel growth in many types of tumors, which was being studied as a potential cancer drug opportunity.
 
After creating fruit flies lacking the enzyme, the team studied them in comparison to normal flies via metabolomics. The team was surprised to find that while the mutant flies no longer produced lactate dehydrogenase, they lacked L-2HG as well, indicating that the enzyme was responsible for L-2HG production. This led to further analysis of the unmodified flies and found that they normally produce the molecule at high levels in the larval stage, during which the body grows over 200 times in size over several days. They also identified a new mechanism that allowed the flies to control their accumulation of the molecule. While the flies manage to precisely control the manufacture of L-2HG, its production in cancer and diseased cells is unregulated.
 
L-2HG has been found in tumor cells from patients with brain and kidney cancers. What makes this research of particular interest is that it is the first to show how the molecule functions in a healthy animal, enabling a deeper understanding of what impacts accumulation of the molecule, and how to arrest rampant growth in diseased bodies.
 
“How the function of L-2GH differs between healthy and diseased tissues is poorly understood,” Tennessen said. “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.”
 
According to Tennessen, the IU team will continue its research using the fly model as a means of understanding how L-2HG functions in normal, healthy cells. They plan to continue studying this molecule during Drosophila larval development as a means of identifying the endogenous targets of L-2HG.
 
States Tennessen, “My lab is primarily interested in using Drosophila larval growth as a model for studying a unique form of carbohydrate metabolism known as aerobic glycolysis or the Warburg effect, which is the metabolic state commonly associated with proliferating cancer cells. We’ve previously demonstrated that rapidly growing fly larvae rely on a variation of the Warburg effect to support rapid growth. Our discovery that flies generate L-2HG during this developmental stage provides the first evidence that growing cells can generate this molecule as byproduct of aerobic glycolysis. As a result, our focus has shifted towards studying the links between aerobic glycolysis and L-2HG metabolism.”
 
The long-term goal of this research is to identify the L-2HG sensitive mechanisms that are conserved between flies and human, and ultimately translate their discoveries into a clinical context, though the timeline for clinical application remains vague.
 
“Since we are currently focused on exploring the basic biology that underlies L-2HG function, we’re uncertain about the time it will take to translate our findings into a commercial product,” notes Tennessen. “We have no immediate plans to transition our research into a clinical setting. However, our hope is to collaborate with scientists and physicians who would like to translate our findings into a clinical setting.”
 
Further research will explore how the L-2HG molecule functions in a healthy animal, and what precisely happens when there is too much, or not enough present, and what specific genes might be controlled by the molecule. They will also be exploring the relationship between L-2HG and other disorders beyond cancer, as well as how the enzyme impacts a mirror version of the molecule known as D-2HG which has also been linked to brain tumors and leukemia.
 
“While L-2HG has recently emerged as a putative oncometabolite, my lab is also interested in using the fly model to study a class of rare genetic diseases known as the 2-hydroxyglutaric acidurias. These are rare and poorly understood inborn errors of metabolism. We plan to use the fly as a model for studying the metabolic defects that underlie these disorders,” he said.
Code: E031701

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