Researchers are beginning to understand why certain brain cancers are so hard to stop.
Three studies published Wednesday in the journal Nature found that these deadly tumors integrate themselves into the brain's electrical network and then hijack signals from healthy nerve cells to fuel their own growth.
But the research offers hope as well. Scientists say the findings suggest that some brain tumors could be slowed with drugs that inhibit the activity of certain brain cells or that interrupt connections between tumor cells and healthy cells.
Two of the three studies, including Winkler's, looked at high-grade gliomas, which include glioblastoma, the cancer that killed Sen. John McCain in 2018.
"High-grade gliomas are really an intractable set of diseases, and we've made very little progress clinically in effectively treating these terrible brain cancers," says Dr. Michelle Monje, an associate professor of neurology and neurological sciences at Stanford University and an author of a second study.
In 2015, Monje was part of a team that found high-grade gliomas grew faster when the brain cells around them became more active.
Monje's team suspected that was because active neurons produce a substance that acts like fuel for gliomas. So the team placed human glioma tumors in the brains of mice that had been genetically altered so they couldn't produce this substance.
"There wasn't just a slowing in the tumor growth — there was a complete stagnation," Monje says. The study was published in 2017.
In people, though, Monje was pretty sure that high-grade gliomas were somehow causing healthy brain cells to become more active and produce more fuel. And she thought the cancer cells might be doing this by forming connections with healthy neurons and hijacking the electrical signals they produce
The new studies appear to confirm this, and even show how.
Monje's team found that some cancer cells were forming synapses — the connections between neurons — that could be seen with an electron microscope. They also found evidence of a more primitive direct connection between cancer cells and healthy brain cells.
Tumor cells "are integrating into neural circuits in the brain," Monje says, then using these connections to affect the behavior of neurons. "The cancer cells themselves are promoting the neuronal activity that then feeds back to drive the growth of the cancer."
Winkler and his team found virtually the same thing with a different set of glioma cells. "There's a massive amount of networking going on," he says.
A third study, led by researchers in Switzerland, found that when breast cancer cells move to the brain, they also can form connections with neurons.
The research is likely to have a seismic impact on brain cancer research, says Andres Barria, a neuroscientist at the University of Washington who studies synapses and wrote an editorial accompanying the three studies.
"My reaction was, wow," he says. "To show that [a tumor cell] actually makes real connections just like normal neurons will do is very amazing."
And that discovery could lead to new and better treatments for high-grade gliomas, which now typically kill a patient within two years.
"Our hope is that by decreasing the electrical signals that the tumors are receiving from the normal brain, that we might be able to complement existing therapies and extend survival and improve quality of life," Monje says.
Her team showed that an anti-epilepsy drug called perampanel reduced the growth rate of one type of glioma by 50% in mice.
But Barria advises caution when it comes to drugs that affect the connections between brain cells.
"Synapses are everywhere in the brain," he says. "So to target only the synapses between cancer cells and neurons, that's what's going to be tricky."