Brain tumours caused by normal neuron activity in mice predisposed to such tumours

26 May 2021
Brain tumours caused by normal neuron activity in mice predisposed to such tumours

Seeing, hearing, thinking, daydreaming - doing anything at all, in fact - activates neurones in the brain.

But for people predisposed to developing brain tumours, the ordinary buzzing of their brains could be a problem.

A study by researchers at Washington University School of Medicine in St. Louis and Stanford University School of Medicine shows that the normal day-to-day activity of neurones can drive the formation and growth of brain tumours.

The researchers studied mice genetically prone to developing tumours of their optic nerves, the bundle of neurones that carries visual signals from the eyes to the brain.

The mice served as a model for children with the genetic condition neurofibromatosis type 1 (NF1).

About one in six children with NF1 develops low-grade optic nerve tumours by age 7.

In this study, mice with Nf1 mutations raised under normal lighting developed tumours; those kept in the dark during a critical period of development did not.

The findings, published in the journal Nature, suggest that neuronal activity plays an under-appreciated role in nervous system cancers.

The research opens up new avenues to preventing brain tumours in children at high risk for them.

"Optic gliomas are very common in children with NF1, and they can cause vision loss," said co-senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology at Washington University and the director of the university's NF Center. "We don't have a good way to predict who will develop tumours or any way to prevent them. But now that we know these brain tumours are caused by exposure to light and neuronal activity, we can start thinking of next-gen prevention strategies. Maybe we can give kids cool sunglasses to wear with filters or lenses to block out certain wavelengths of light, or repurpose drugs that suppress excessive neuronal activity, and protect these kids from developing brain tumours and losing their sight."

Co-senior author Michelle Monje, MD, PhD, an associate professor of neurology at Stanford Medicine, previously demonstrated that neuronal activity drives the growth of an aggressive form of brain cancer.

But it wasn't clear whether neuronal activity itself sets in motion the process of tumour formation or if it only bolsters the growth of tumours initiated by other processes.

As part of this study, the researchers used mice with mutations in their Nf1 gene.

Such mice start developing low-grade tumours of their optic nerves around 9 weeks of age, and virtually all have tumours by 12 weeks to 16 weeks old.

Since the neurones in the optic nerve become active when exposed to light, the researchers investigated whether they could reduce neuronal activity - and, thereby, tumour formation - simply by keeping the mice away from light.

They raised mice from age 9 weeks to 16 weeks in the dark and then checked for tumours.

"The results were so striking. Mice raised in the dark simply did not develop tumours, while all the mice raised in the light did, despite their identical genetic predisposition to develop optic nerve tumours," Monje said. "While we had previously found that neuronal activity is an important regulator of glioma growth, these findings showed how crucial neuronal activity can be for tumour formation."

Further experiments verified the crucial role of light exposure and narrowed down the critical window to age 6 weeks to 12 weeks.

None of the mice reared in the dark during that time frame developed tumours by 24 weeks of age.

Putting mice older than 12 weeks, when the tumours already had formed, into darkness slowed tumour growth but did not shrink them.

First author Pan Yuan, PhD, who first worked with Gutmann at Washington University and is now a postdoctoral researcher with Monje, showed that the link between light and tumours requires a protein called neuroligin 3.

When their optic nerves are stimulated, mice with Nf1 mutations release abnormally high levels of neuroligin 3.

Blocking the protein with a drug or genetically modifying mice to eliminate the neuroligin 3 gene resulted in fewer and smaller tumours.

Moreover, brain tumours from people are also high in neuroligin 3, which suggests the possibility of targeting the protein as a treatment for brain tumours.

The researchers analysed tissue samples from 19 people with low-grade brain tumours and found high levels of neuroligin 3, regardless of whether they arose in children with NF1 or not.

"All of this is teaching us that we may have ignored one really important cell type in nervous system cancers: the neurone," Gutmann said. "As neurologists, we have been treating overactive neurones for decades with drugs. One of the directions our laboratories are pursuing is repurposing some of those drugs to see if we can shut off unwanted activity, maybe just for a short developmental period, and prevent brain tumours from forming. And there are other points at which we could intervene as well: by limiting light exposure, by targeting neuroligin 3 or inhibiting some other step in the pathway. It has really opened our eyes."

Source: Washington University School of Medicine