To Fuel Their Growth, Cancer Cells Hijack Neurons

Glioblastoma, the most common type of brain cancer, is aggressive and recurrent, and the prognosis is grim: median survival is less than 18 months and the 10-year survival rate is 0.71 percent.^1,2 Patients diagnosed with a glioblastoma can suffer from altered speech, movement, and even personality, depending on where in the brain the tumors amass.³ Part of the broader group of gliomas, glioblastoma originates in glial cells, the most abundant cell type in the brain.

Two neuro-oncologists have received this year’s Brain Prize for identifying how cancer cells hijack nerve cells in the brain in glioblastoma. The discovery was made separately but simultaneously by Frank Winkler of Heidelberg University and Stanford University’s Michelle Monje. The pair’s research has inspired a new field, cancer neuroscience, and changed how researchers and clinicians study and even operate on brain tumors. Winkler and Monje will share a cash prize of 10 million Danish kroner (roughly $1.4 million), the world’s largest award for neuroscience research. This research has been a long time coming; clinicians providing care to those affected by glioblastoma said that they have been fighting a losing battle for decades.

The Difficult Decisions in Glioblastoma Surgery

A few hours before he cuts a cancerous lump from the brain of one of his patients, Ola Rominiyi, a neurosurgeon at the University of Sheffield, checks to make sure they have taken the “pink drink”. This isn’t a strawberry milkshake, but 5-aminolevulinic acid (5-ALA), an unremarkable, slightly bitter, and disappointingly colorless concoction mixed with water. It’s only when patients are deeply anesthetized that 5-ALA works its magic. The compound makes brain tumors glow an unearthly pink under a fluorescent light. When combined with a brain scan, 5-ALA helps the surgical team spot tumors. Even with this assistance, Rominiyi and his team still face a difficult decision during every surgery: Where should they cut?

“It's really difficult to know what is the appropriate and best time to stop so that I'm getting as much of the tumor as possible to help those patients live longer while still minimizing the risk of causing damage,” said Rominyi.

The core of a brain tumor is relatively easy to spot, Rominiyi noted, adding, “As you get to the middle of the tumor, the cells have been growing so quickly they've outstripped their ability to get enough oxygen. Some of those cells start to die.” This produces gray or black necrotic tissue. But this rotten center is surrounded by a border region populated by seemingly healthy neurons.

Curious about the cellular landscape in these borderlands between brain and tumor, Rominiyi and his team collected a sample of brain tissue, taken centimeters from where their MRI guide said the tumor ended. “Ten to 15 percent of the cells were tumor cells,” said Rominiyi.

Despite the surgical teams’ best efforts to capture as much of the cancer as possible, the tumors usually reappear within a year.⁴ “Recurrence is inevitable,” said Rominiyi. These grim realities illustrate an important point: Before Monje and Winkler’s research, brain surgeons like Rominiyi were operating with one arm tied behind their backs. That’s because we didn’t yet know how aggressively gliomas worm their way into the brain.

Frank Winkler of Heidelberg University uses advanced microscopy and other neuroscientific methods to study how cancer cells interact with neurons.

Frank Winkler

In 2014, Winkler moved to Heidelberg to take up a professorship in experimental neuro-oncology. For years he had been studying metastasis, but he decided to set his sights on a new challenge: understanding gliomas. He was curious whether the microstructure of tumors could reveal any hints about their incredible persistence. To get a glimpse of the tumors in vivo, he used a microscopy technique he was first introduced to over a decade earlier during a research fellowship at Harvard University. Multiphoton imaging uses powerful microscopes to see more deeply into biological tissues than single-photon approaches.

His team implanted patient tumor stem cells into mice and inserted cranial windows into the animals’ heads in order to look directly at the growing tumor cells using the multiphoton microscope.⁵ “We saw that these tumor cells extend very long protrusions—thin membrane tubes—into the brain,” said Winkler. He took samples to his colleague Felix Sahm, a neuropathologist at Heidelberg University Hospital, to see what he made of the unusual structures. After two hours, he got a call back. “They are everywhere,” Sahm said. The brains were riddled with the rootlike growths, which Winkler would later call tumor microtubes.

A “Crazy” Discovery Reveals How Cancer Binds to the Brain

As a medical student at Stanford University, Monje helped care for a child with diffuse intrinsic pontine glioma, a disease that was, and remains, lethal. This affected her deeply and seeded a career-long interest in what makes these tumors tick. During her years in neurology training, Monje began to suspect that brain activity played some role in glioma pathology. Gliomas often manifest in particularly plastic brain areas, such as regions that recovered following a stroke. Also, in a cruel twist, tumors seem to affect brain regions that patients engaged regularly. For example, gliomas struck ballet dancers in their cerebellar vermis, which controls posture, and university professors in their brains’ language centers.

Michelle Monje of Stanford University studies neuron-glial interactions in health and disease.

Michelle Monje

By 2015, Monje had an independent lab at Stanford University and access to the tools required to explore this link between brain activity and glioma. Their research hinged on optogenetics, which they used to turn individual genes on and off by exposing them to light. They showed that neuronal activity pumped up glioma networks, as if the cancer fed off the brain’s electrical activity.⁶ The glioma cells were also hijacking molecular signals and exploiting a molecule called neuroligin-3 to boost their expansion throughout the brain.

Later that year, Winkler invited Monje to Heidelberg University to give a lecture. Sitting together in Winkler’s office, Monje shared her new findings. Winkler remembers her words: “Frank, I think we discovered something crazy.”

“No, Michelle. I think we discovered something crazy,” Winkler replied. After swapping notes, the two researchers realized they had independently identified the same process. “What Monje and Winkler discovered is that the gliomas don't just grow in the brain, they actually become wired into it,” said Johanna Joyce, an oncologist at the University of Lausanne.

Winkler and Monje continued their contact. This collaboration culminated with a pair of studies published in the same issue of Nature in 2019 that documented their most unexpected finding.^7,8 This research showed that cancer cells form synapses with neurons that function like excitatory neuronal synapses. These synapses allowed the glioma to exploit the brain’s neural activity, like a sneaky neighbor feeding off next door’s electricity supply.

The two labs continued their work in parallel. Winkler’s team identified a small population of cancer cells that rhythmically pulsed in response to calcium currents flowing through the hijacked synapses.⁹ “They are the pacemakers,” Winkler explained. These cells’ rhythms are a drumbeat that further amps up glioma growth. When the team physically destroyed these cells, or pharmacologically suppressed them, tumor development drastically slowed. Monje showed that glioma-neuron synapses were plastic and could change in response to brain-derived neuronal factor (BDNF), a protein that supports neuronal growth.¹⁰

Pioneers of Cancer Neuroscience

Winkler and Monje’s work has birthed a new field called cancer neuroscience. “Michelle and Frank have opened up this idea that brain cancer is not like any other cancer,” said Mario Suva, a neuro-oncologist at Harvard Medical School. Researchers and clinicians have long prioritized the biology of tumor cells when studying how cancer grows and spreads. Now, the focus has shifted to brain cancers’ uniquely electrical environment and the pro-growth influence of neuronal activity. This change has provided new targets for combating these fierce diseases.

These new therapies, championed by Winkler and Monje, target glioma cells’ access to their hijacked resources. Perampanel is an antiepileptic drug that suppresses the same type of receptors glioma cells use to feed off the brain. In a new clinical trial, Winkler is testing the drug on patients with recurrent brain cancer.¹¹ His team has also begun work on two separate trials using drugs that target tumor microtube structure and pacemaker cells.¹² Monje is developing a drug to stop the tumors’ access to neuroligin-3.¹³ This multi-pronged approach is canny as it’s likely that any successful treatment will be a combination of multiple interventions. “I don't think there will be one silver bullet,” said Rominiyi.

Monje and Winkler’s research may ultimately change cancer beyond the brain. “Our body is full of nerves,” said Winkler. “Everything is innervated in our body, so nerves can control our bodily functions. But nerves also control tumors throughout our body.” Multiple cancer fields have now shown that tumors can feed off peripheral nerve cells’ activity like gliomas do in the brain.^14,15 Suva compared this discovery to the identification of angiogenesis, where tumors establish a blood supply to receive nutrients. “The other part of the growth signal can also come from nerves,” he added.

What experts say is most encouraging is that the field’s ideas about how brain cancers spread have been enthusiastically adopted. Winkler said that this is partly down to the independent work from his and Monje’s labs, which offer a robust evidence base. He added that cancer neuroscience’s main theories confirmed suspicions that neuro-oncologists and neurosurgeons had about gliomas’ bouncebackability but had been unable to prove.

For Rominiyi, who is part of a new generation of brain surgeons, insights from cancer neuroscience light the way to finally beating brain cancer. More research and investment will be essential. “We can find the best ways of tackling those connections between the tumor cells and the healthy brain without impacting those connections between normal brain cells that are fundamental to who we are and how we think and what we do,” he concluded.

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