Researchers have made a discovery about genes that are adjacent to each other; they can fuse, which boosts the activity of organelles called mitochondria. That can drive cell growth and can cause cancer. The scientists from Columbia University Medical Center (CUMC) also found that when drugs act to interfere with this novel cancer pathway, it can halt tumor growth in a mouse model of brain cancer and human cells in culture. The work was reported in the journal Nature and is outlined in the video.
The CUMC researchers have already shown that when the genes FGFR3 and TACC3 fuse, it can cause one of the most aggressive forms of primary brain cancer. It had been thought that this phenomenon was limited to only a small percentage of brain tumors, impacting around 300 people in the United States annually. Recent studies have told a different tale.
That same gene fusion has been observed in subsets of breast, esophageal, lung, head and neck, cervical and bladder cancers, which translates to thousands of patients. "It's probably the single most common gene fusion in human cancer," noted the co-leader of the work, Antonio Iavarone, MD, professor of neurology and of pathology and cell biology in the Institute for Cancer Genetics at CUMC. "We wanted to determine how FGFR3-TACC3 fusion induces and maintains cancer so that we could identify novel targets for drug therapy."
This work has shown that in cells with fused FGFR3-TACC3 genes, the activity of the cellular powerhouse, the mitochondria, is substantially increased. Scientists have known for some time that cancer is linked to changes in mitochondria and cellular metabolism. Cancer cells need very active mitochondria to drive their rapid growth. This research may reveal how gene mutations are connected to altered mitochondrial activity and tumor development.
The scientists also found that the fusion of FGFR3 and TACC3 activated the PIN4 protein, which then moves to an organelle called the peroxisome. Peroxisome production is increased, and oxidants are released, which act on a molecule that regulates metabolism in the mitochondria. The outcome is an uptick in mitochondrial activity and the production of energy.
"Our study offers the first clues as to how cancer genes activate mitochondrial metabolism, a crucial and longstanding question in cancer research, and provides the first direct evidence that peroxisomes are involved in cancer," explained a co-leader of the report, Anna Lasorella, MD, professor of cell biology in the Institute for Cancer Genetics and of pediatrics at CUMC. "This gives us new insights into how we may be able to disrupt cancer's fuel supply."
When the investigators exposed brain cancer cells with FGFR3-TACC3 fusions to chemicals that inhibit mitochondria activity, energy production went down and tumor growth slowed. A mouse model repcaitualted those results.
This work can help create new therapeutic options. A kinase inhibitor has been found to interfere with the protein produced by the fused genes. There are currently clinical trials evaluating the efficacy of such a drug in patients with gene fusion.
"Drugs that inhibit active kinases have been tried with encouraging results in some cancers," said Dr. Iavarone. "But invariably, they become resistant to the drugs, and the tumors come back. However, it may be possible to prevent resistance and tumor recurrence by targeting both mitochondrial metabolism and FGFR3-TACC3 directly."
Next, the team wants to see whether adding mitochondrial inhibitors to patient therapeutics will help patients. They are now testing this approach in cell culture and animal models.