Researchers have been struggling with what fuels cancer cell growth. For more than 75 years, researchers have known that cancer cells use glucose as the major fuel, but efforts to halt cancer growth by controlling glucose levels in the brain haven’t worked.
“We identified that glucose wasn’t the only fuel being burned,” said senior author Dr. Robert Bachoo, Assistant Professor of Neurology and Neurotherapeutics, and Internal Medicine, and a member of the Harold C. Simmons Cancer Center. “Acetate can be used to generate fuel and metabolites that can then be used to make other things that the cell needs to survive and multiply.”
Researchers began with specially engineered mouse models so that the tumors grown in the brain were very similar to human tumors, especially with respect to the molecular and metabolic characteristics. They then infused both 13C-acetate and 13C-glucose into the mice and were able to show that the tumors burn acetate as fuel.
“This is the first demonstration of acetate being used by the cell in this way. The striking finding was that all cancers we studied had the same ability to burn acetate,” said Dr. Elizabeth Maher, Associate Professor of Internal Medicine, and Neurology and Neurotherapeutics, and member of the Harold C. Simmons Cancer Center and the Annette G. Strauss Center for Neuro-Oncology, who holds the Theodore H. Strauss Professorship in Neuro-Oncology. “All the tumors we studied increased expression of ACSS2, the acetate metabolizing enzyme, and the gliomas appear to be dependent on acetate for growth.”
Researchers then validated their findings in two patients with glioblastomas and two patients with brain metastases (breast and lung cancer) who were undergoing surgical resection of their tumors.
“That analysis showed that the human tumors robustly burned acetate,” said Dr. Bachoo, a member of the Annette G. Strauss Center for Neuro-Oncology, who holds the Miller Family Professorship in Neuro-Oncology. “ACSS2 may thus be a therapeutic target for these very aggressive tumors that have limited therapies available.”
Combined with related research, an accompanying Preview article in the journal Cell suggested that “the insights provided by these studies position acetate metabolism as a potentially exploitable vulnerability in cancer metabolism.”