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Research on a Rare Cancer Exposes Possible Route to New Treatments

SALT LAKE CITY—Researchers from Huntsman Cancer Institute (HCI) at the University of Utah (U of U) discovered the unusual role of lactate in the metabolism of alveolar soft part sarcoma (ASPS), a rare, aggressive cancer that primarily affects adolescents and young adults. The study also confirmed that a fusion gene is the cancer-causing agent in this disease. The research results were published online in the journal Cancer Cell November 26.

ASPS tumor cells contain a chromosomal translocation—strands of DNA from two chromosomes trade places. The two strands fuse together to create 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 U of U, and his research team activated the ASPSCR1-TFE3 gene in mice. The cancer was completely penetrant; every mouse with the activated fusion gene developed a tumor.

"The mouse tumors were remarkably similar to human ASPS tumors," said Jones. "The fusion gene not only initiates a cancer in the mouse, it initiates all the features we associate with this cancer in humans, including nearly identical RNA profiles." This is especially important in the study of sarcoma, as few human cell lines exist.

Jones said one surprising finding of the study was the location of the tumors in mice. 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.

"The two places where we found most of the mouse tumors—inside the brain and inside the orbit of the eye—had the highest concentrations of lactate," said Jones. "The tissues where ASPS occurs in humans, the skeletal muscles, also have high concentrations of lactate."

Most cancer cells generate their energy in a process called glycolysis, in which they rapidly but inefficiently consume glucose. This process creates lactate as a waste product that the cancer cells push 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 that made the cells behave as if they were in a low-oxygen environment," said Jones. "It's unusual to find a cancer using lactate this way. The ASPS cells grow preferentially where they are bathed in high concentrations of lactate."

Future work in this area could include finding ways to block the cancer cells' uptake of lactate to starve them or render them less aggressive, according to Jones. "In the broader picture of trying to understand the metabolism of cancer—the way cancer cells interact with their environment and produce energy—we can work on discovering their unique vulnerabilities," he said. "That would be the ideal route to new and effective treatments.

"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," said Jones. "Our study confirmed that the fusion gene ASPSCR1-TFE3 causes ASPS; it's the driver."

Only 50 to 100 cases of ASPS are diagnosed in the United States each year, but this research bears on a fundamental question of cancer research: "How does a cancer start?" Initiating most common cancers requires many genetic mistakes in the affected cells, and as the cancer grows even more mistakes are gained. Jones said that this study, as well as others looking at cancers initiated by the single event of a chromosomal translocation and the resulting fusion gene, may provide a "clearer lens through which to look at the fundamental biology of cancer's patterns of development."

The article's co-authors include Matthew Goodwin, MD, PhD; Huifeng Jin; Kyllie Smith-Fry; and Michael Monument, MD, of HCI's K.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.

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About Huntsman Cancer Institute at the University of Utah

Huntsman Cancer Institute (HCI) is one of the world's top academic research and cancer treatment centers. HCI manages the Utah Population Database - the largest genetic database in the world, with more than 16 million records linked to genealogies, health records, and vital statistics. Using this data, HCI researchers have identified cancer-causing genes, including the genes responsible for melanoma, colon and breast cancer, and paraganglioma. HCI is a member of the National Comprehensive Cancer Network (a 25-member alliance of the world's leading cancer centers) and is a National Cancer Institute-Designated Cancer Center. HCI treats patients with all forms of cancer and operates several high-risk clinics that focus on melanoma and breast, colon, and pancreas cancers. The HCI Cancer Learning Center for patient and public education contains one of the nation's largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, Sr., a Utah philanthropist, industrialist, and cancer survivor.

Kevin B Jones