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. Patients diagnosed with a glioblastoma can suffer from altered speech, movement, and even personality, depending on where in the brain the tumors amass. 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. “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.
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. “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.
