Gene Fusion Shifts Cell Activity Into High Gear, Causing Some Cancer
Source: Columbia University Medical Center
Summary: Researchers have discovered that the fusion of two adjacent genes can cause cancer by kicking mitochondria into overdrive and increasing the amount of fuel available for rampant cell growth.
Gene fusion is a process where two or more distinct genes are fused into a single chimeric gene. It can occur as a result of chromosomal translocations or inversions. In a previous study, researchers have found that some cases of glioblastoma, the most common and aggressive form of primary brain cancer, are caused by the fusion of two genes, FGFR3 and TACC3. However, same gene fusion has been observed in a percentage of lung, esophageal, breast, head and neck, cervical, and bladder cancers, affecting tens of thousands of cancer patients overall. Researchers from the Columbia University Medical Center have discovered that the fusion of two adjacent genes can cause cancer by kicking mitochondria into overdrive and increasing the amount of fuel available for rampant cell growth. They also found that drugs that target this newly identified cancer pathway can prevent tumor growth, both in human cancer cells and mice with a form of brain cancer. The research findings were published in the journal Nature.
Researchers have found only recently that mitochondrial activity and cellular metabolism are linked to certain cancers. However, the mechanism by which genetic mutations alter mitochondrial activity and promote tumor growth was unknown.Using a variety of experimental techniques, the research team determined that the gene fusion initiates a cascade of events that increase mitochondrial activity. First, FGFR3-TACC3 activates a protein called PIN4. Once activated, PIN4 travels to peroxisomes, cellular structures that break down fats into substances that fuel mitochondrial activity. Activated PIN4 triggers a four-to-five-fold increase in the production of peroxisomes, which release a flood of oxidants. Finally, these oxidants induce PGC1alpha, a key regulator of mitochondrial metabolism, to increase mitochondrial activity and energy production. Based on the findings of this study, the team is considering the possibility of adding mitochondrial inhibitors into the therapeutic mix for patients in the trial.
Study co-leader Antonio Iavarone said, “Drugs that inhibit active kinases have been tried with encouraging results in some cancers”, “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.”
More Information: Veronique Frattini et al, “A metabolic function of FGFR3-TACC3 gene fusions in cancer”, Nature (2018).nature.com/articles/doi:10.1038/nature25171