Gene fusion shifts cell activity into high gear, causing some cancer

January 3, 2018, Columbia University Medical Center
Central nervous system cells expressing the FGFR3-TACC3 fusion protein. Credit: Iavarone Lab, Columbia University Medical Center

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, researchers at Columbia University Medical Center (CUMC) have discovered. 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 study was published online today in the journal Nature.

In a 2012 study published in Science, the CUMC team found that some cases of glioblastoma, the most common and aggressive form of primary , are caused by the of two genes, FGFR3 and TACC3. At the time, it was thought that this gene fusion was limited to a fraction of brain tumors, affecting about 300 patients in the U.S. per year.

Since then, however, other researchers have observed the same gene fusion in a percentage of lung, esophageal, breast, head and neck, cervical, and bladder cancers, affecting tens of thousands of cancer patients overall. "It's probably the single most common gene fusion in human cancer," said study co-leader 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."

Changes in mitochondria—the 'powerhouse' of the cell—have been observed in cancer for a long time, but 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.

In the current study, the CUMC researchers compared the activity of thousands of genes in cancer cells with and without FGFR3-TACC3. They discovered that the fusion greatly increases the number and accelerates the activity of mitochondria. Cancer cells, which require huge amounts of energy to rapidly divide and grow, can thrive when mitochondrial activity has been amped up.

Using a variety of experimental techniques, the researchers determined that the gene fusion initiates a cascade of events that increases 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 and energy production.

"Our study offers the first clues as to how cancer activate mitochondrial metabolism, a crucial and longstanding question in cancer research, and provides the first direct evidence that peroxisomes are involved in cancer," said study co-leader 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."

In another experiment, treating human brain cancer cells containing FGFR3-TACC3 with mitochondrial inhibitors interrupted the production of energy inside cancer and significantly slowed . The same effect was seen in a mouse model of human brain containing this gene fusion.

Dr. Iavarone suspects that a dual-treatment approach may be needed for patients with FGFR3-TACC3 tumors. In their previous study, the researchers found that drugs that inhibit FGFR3 kinase, an enzyme that helps the protein produced by this fusion gene do its work, increased survival when tested in mice with glioblastoma.

These drugs are now being tested in patients with recurrent glioblastoma that contains the by one of the paper's co-authors, Marc Sanson, MD, of Pitié Salpêtrière Hospital in Paris. "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."

Based on the findings in this study, the team is now considering the possibility of adding mitochondrial inhibitors into the therapeutic mix for patients in this trial.

The CUMC team is currently testing this dual approach in human and animals models.

Explore further: New link seen between gene fusion and bladder cancer

More information: A metabolic function of FGFR3-TACC3 gene fusions in cancer, Nature (2018). nature.com/articles/doi:10.1038/nature25171

Related Stories

New link seen between gene fusion and bladder cancer

September 18, 2017
(HealthDay)—The fibroblast growth factor receptor 3 (FGFR3) transforming acidic coiled-coil containing protein 3 (TACC3) (FT3) gene fusion recruits endogenous TACC3 away from the mitotic spindle, resulting in errors in ...

Study highlights new link between gene fusion and bladder and brain cancer

August 30, 2017
A study by the University of Warwick sheds new light on gene fusion in bladder and brain cancer.

Fusion gene contributes to glioblastoma progression

January 9, 2013
Fusion genes are common chromosomal aberrations in many cancers, and can be used as prognostic markers and drug targets in clinical practice.

Genetic alterations show promise in diagnosis and treatment of bladder cancer

October 16, 2013
A Chinese research team composed of Shenzhen Second People's Hospital, BGI and other institutes reports their latest study on bladder cancer genomics that was published online in Nature Genetics. The discoveries were made ...

Genetic targets to chemo-resistant breast cancer identified

October 3, 2017
Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Study reveals genes that drive brain cancer

August 5, 2013
A team of researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center has identified 18 new genes responsible for driving glioblastoma multiforme, the most common—and most aggressive—form ...

Recommended for you

Pregnant? Eating broccoli sprouts may reduce child's chances of breast cancer later in life

August 16, 2018
Researchers at the University of Alabama at Birmingham have found that a plant-based diet is more effective in preventing breast cancer later in life for the child if the mother consumed broccoli while pregnant. The 2018 ...

Three scientists share $500,000 prize for work on cancer therapy

August 15, 2018
Tumors once considered untreatable have disappeared and people previously given months to live are surviving for decades thanks to new therapies emerging from the work of three scientists chosen to receive a $500,000 medical ...

PARP inhibitor improves progression-free survival in patients with advanced breast cancers

August 15, 2018
In a randomized, Phase III trial led by researchers at The University of Texas MD Anderson Cancer Center, the PARP inhibitor talazoparib extended progression-free survival (PFS) and improved quality-of-life measures over ...

New clues into how 'trash bag of the cell' traps and seals off waste

August 15, 2018
The mechanics behind how an important process within the cell traps material before recycling it has puzzled scientists for years. But Penn State researchers have gained new insight into how this process seals off waste, ...

RUNX proteins act as regulators in DNA repair, study finds

August 15, 2018
A study by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore has revealed that RUNX proteins are integral to efficient DNA repair via the Fanconi Anemia (FA) ...

Chemicals found in vegetables prevent colon cancer in mice

August 14, 2018
Chemicals produced by vegetables such as kale, cabbage and broccoli could help to maintain a healthy gut and prevent colon cancer, a new study from the Francis Crick Institute shows.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.