Overlooked portion of gene fusion may worsen bladder and brain cancers

Liz Meszaros, MDLinx | August 30, 2017

Researchers from the University of Warwick have discovered that a previously overlooked part of the gene fusion process may actually worsen both bladder cancers and brain cancers. They published their results in the journal Open Biology.

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Looking at gene fusion differently

Researchers found that the TACC3 fusion causes cell division mistakes, and thus makes cancer worse.

Gene fusion, or the fusion between one gene and another to make a new gene, occurs when chromosomes break and reattach to a different chromosome in an unusual way.

The gene fusion FGFR3-TACC3 is associated with both bladder cancers and brain cancers, and scientists at Warwick Medical School sought to study it further. Instead of focusing on the first half of the fusion—FGFR3, which has a known association with cancer, they studied the second half of the fusion, transforming acidic coiled-coil protein 3 (TACC3).

They found that the TACC3 fusion causes cell division mistakes, and thus makes cancer worse.

“Cancer cells often have gene fusions which happen because the DNA in cancer cells is really messed up such as the well-known Philadelphia chromosome in chronic myelogenous leukemia,” said lead researcher Stephen Royle, BSc, PhD. “A few years ago, a new fusion was discovered in bladder and brain cancers, called FGFR3-TACC3. Previously most of the emphasis has been on the former part of the fusion. However we found that the latter part of the fusion causes mistakes in cell division which could make the cancer worse.”

During cell division, TACC3 helps chromosomes separate. The chromosomes are then shared out by the mitotic spindle inside the cell, which is comprised of microtubules. TACC3 acts to stabilize these microtubules and strengthen the mitotic spindle. Previous research has suggested that the gene fusion FGFR3-TACC3 may bind to the mitotic spindle but somehow malfunction.

Indeed, Dr. Royle and colleagues found that FGFR3-TACC3 does not bind to the mitotic spindle, but to the cell membrane and in small intracellular vesicles. Thus, the TACC3 section of the fusion gene FGFR3-TACC3 acted as a vacuum cleaner, cleaning the normal TACC3 off the spindle, and thus preventing normal cell division.

Normal TACC3 repaired this faulty division, and removal of the FGFR3-TACC3 fusion also returned cells back to normal.

“Doing work like this is important as it helps us to understand all the possible ways to tackle a specific cancer and to find any problems with potential treatments,” said Dr. Royle. “An ideal cancer treatment might be to block TACC3 interactions as well as stopping signaling. However this is very difficult to do and is far in the future. Drug companies can develop chemicals which stop cell signaling from fusions and these could work as anti-cancer agents,” he concluded.

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