An Unusual Role for Lactate in a Rare Sarcoma's Cells

Cancer research is based on some fundamental questions: How does a cancer start? And what does it need to survive? Researchers from the Kevin B. Jones Lab at Huntsman Cancer Institute (HCI) set out to study a rare sarcoma. The answers they found to these questions may help redefine what’s possible in treating it.

Jones’ research focused on alveolar soft part sarcoma (ASPS), a rare, aggressive cancer that primarily affects adolescents and young adults. ASPS tumor cells contain a chromosomal translocation—arms of DNA from two chromosomes trade places. The point where the two arms fuse together creates a new gene, ASPSCR1-TFE3, that functions differently than either “parent” gene.

For the study, Kevin B. Jones, MD, an HCI investigator and assistant professor in the Department of Orthopaedics at the University of Utah, and his research team studied mice with the ASPSCR1-TFE3 fusion gene. Every mouse with the gene developed a tumor.

“When we find a translocation and fusion gene associated with a specific cancer, the question is always whether it drives the cancer or is a passenger created through the cancer’s action on the tumor cells,” says Jones. “Our study confirmed that the fusion gene ASPSCR1-TFE3 causes ASPS; it’s the driver.”

One surprising finding of the study was where the mouse tumors occurred. In humans, most ASPS tumors occur in skeletal muscle, but all the mouse tumors occurred within the skull—not necessarily in brain tissue, but within the environment of the cranium.

“We confirmed that one unique characteristic of the environment inside the cranium is that it has the highest concentrations of lactate,” says Jones. Lactate is one of a group of molecules involved in energy production in cells. “The tissues where ASPS occurs in humans also have high concentrations of lactate.”

Most cancer cells generate their energy in a process called glycolysis. They rapidly but inefficiently consume glucose (a type of sugar and the chief source of energy for living organisms) by breaking it down into lactate. These cancer cells then usually push the waste product, lactate, out into their surroundings.

“In our study, the ASPS tumor cells absorbed lactate from their environment and used it both as a fuel and as a signaling molecule,” says Jones. “ASPS cells grow preferentially where they are bathed in high concentrations of lactate.” Future work in this area includes finding ways to block the cancer cells’ uptake of lactate to starve them or render them less aggressive, according to Jones.

Most common cancers begin in cells that have accumulated many genetic mistakes, and as the cancer grows, even more mistakes happen. This generates complexities that make the study of cancer difficult. Jones says that this study, as well as others looking at cancers that begin from the single event of a chromosomal translocation that creates a fusion gene, rather than the accrual of many genetic mistakes, may provide a “clearer lens through which the fundamental biology of cancer’s patterns of development can be viewed.”

The article’s co-authors include Matthew Goodwin, MD, PhD; Huifeng Jin; Kyllie Smith-Fry; and Michael Monument, MD, of HCI’s Kevin B. Jones Lab. Other co-authors include R. Lor Randall, MD, FACS, an HCI investigator; Mario R. Capecchi, PhD, and Krystal Straessler of the U of U’s Department of Human Genetics; and Allie Grossmann of the U of U’s Department of Pathology. This work was supported by Alex’s Lemonade Stand Foundation, the Sherman Coleman Resident Research Award, the Damon Runyon Cancer Research Foundation, National Cancer Institute grants K08CA138764 and P30CA042014, and Huntsman Cancer Foundation.