Gene fusion as a cause of cancer
The fusion of two neighboring genes enhances the energy production of mitochondria and leads to intensive uncontrolled cell growth, is the result of the work of a group of researchers from Columbia University Medical Center. They also found that drugs that block gene fusion inhibit tumor growth both in human tumor cell samples and in mouse models of brain cancer.
In 2012, a study by the same group of scientists found that some cases of glioblastoma (the most aggressive and common brain tumor) were associated with the fusion of the FGFR3 and TACC3 genes.
Other studies have found fusion processes of the same genes in lung, esophageal, breast, head and neck, bladder and cervix cancers.
The researchers set out to find out exactly how the fusion of these genes is associated with the appearance and development of cancer, as well as to determine whether this mechanism can be used as a target for cancer treatment.
Changes in the mitochondria – the "power stations" of the cell – have been observed in cancer for a long time, but the connection of mitochondrial activity with the development of cancer has been revealed only recently. Exactly how the fusion of genes triggered the work of mitochondria in an enhanced mode remained unknown.
In a new study, a group of scientists compared the activity of thousands of genes in cancer cells with and without gene fusion. They found that FGFR3-TACC3 fusion significantly increases the number of mitochondria and enhances their activity. Cancer cells grow and divide rapidly, so they need a lot of energy, which is possible only with the increased work of mitochondria.
Using various experimental techniques, the researchers found that the fusion of genes triggers a cascade of reactions, eventually leading to an increase in the activity of mitochondria.
The fusion of FGFR3-TACC3 genes activates the PIN4 protein. In the activated state, it moves to peroxisomes – cellular structures in which lipids are broken down to substances that support mitochondria in the active state. PIN4 protein enhances the work of pecroskis 4-5 times. As a result, the production of oxidants increases, which, in turn, induce the PGC1-alpha protein. This protein is one of the most important regulators of mitochondrial metabolism, enhancing energy production.
Cells of the central nervous system that produce protein
after the fusion of the FGFR3 and iTASS3 genes. Source: Iavarone lab.
The study provides the first answers to questions about how mitochondria are activated in cancer cells and energy production increases. It provides evidence of the important role of peroxisomes in this process. This knowledge will help to further develop cancer treatment aimed at blocking the process of gene fusion and stopping the "fuel supply" in the cancer cell.
In experiments conducted on human brain tumor samples containing FGFR3-TACC3, the introduction of mitochondrial inhibitors stopped energy production in cancer cells and significantly slowed tumor growth.
The same result was obtained in a study on mouse models with brain cancer: tumor cells containing FGFR3-TACC3 stopped their growth after the introduction of an inhibitor of mitochondrial metabolism.
The researchers, analyzing the results of their work, write about the possible need for a dual approach to treatment: in addition to inhibitors of mitochondrial activity, they suggest using a drug that inhibits the activity of the enzyme FGFR3 kinase and thus blocks the functions of the protein that is synthesized by the FGFR3-TACC3 genes. The effectiveness of this drug was previously proven by them in a study on mouse models with glioblastoma.
Both of these drugs are being studied among patients with recurrent glioblastoma, in whose cells there is a fusion of FGFR3-TACC3 genes. The FGFR3 kinase inhibitor shows good results when used in isolation, but tumor cells develop resistance to it, and the tumor recurs. The authors of the study hope that its combination with inhibitors of mitochondrial metabolism will solve the problem of relapses and demonstrate sufficient effectiveness.
Article by Véronique Frattini et al. A metabolic function of FGFR3-TACC3 gene fusions in cancer is published in the journal Nature.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on the materials of Columbia University Medical Center: Gene Fusion Shifts Cell Activity into High Gear, Causing Some Cancer.