Brain Tumors Feed off Healthy Neurons

Cancer cells in the brain—be they from primary gliomas or secondary metastases—can form synaptic connections with neighboring neuronal cells in the microenvironment, a trio of studies shows. These synapses, when activated, promote tumor proliferation, survival, and invasiveness. Disrupting the communication channels between neurons and cancer cells could therefore help blunt the growth of deadly brain tumors.

“These papers are amazing,” says Paola Vermeer, PhD, a cancer biologist at Sanford Research in Sioux Falls, SD, who was not involved in the studies. Scientists had previously documented the presence of tumor-infiltrating nerves and shown that patients with densely innervated cancers tend to have worse prognoses, “but this is going a step further,” Vermeer says. “These are bona fide synapses and important for disease progression. We need to take this knowledge and use it to find therapeutics.”

Two of the recently published studies focused on the synaptic cross-talk between gliomas and neurons—and both came to similar, complementary conclusions.

In one, a team led by Frank Winkler, MD, PhD, and Thomas Kuner, MD, of Heidelberg University in Germany, demonstrated that patient-derived glioblastoma samples include excitatory contacts between presynaptic neurons that release glutamate and postsynaptic cancer cells containing long, finger-like protrusions called tumoral microtubes that receive the neurotransmitter signal through AMPA receptors (Nature 2019;573:532–8).

Activating AMPA receptors via optogenetic means stimulated the growth of gliomas transplanted into mice, whereas perturbing glutamate signaling—either genetically or pharmacologically with the antiepileptic drug perampanel (Fycompa; Eisai)—had the opposite effect, reducing the proliferative capacity of the tumors.

Michelle Monje, MD, PhD, of Stanford University in California, and her colleagues independently documented the same types of circuit dynamics in aggressive pediatric brain tumors known as diffuse midline gliomas (Nature 2019;573:539–45).

However, primary brain tumors are not the only cancers capable of co-opting neuronal synapses for their own selfish gain. A group led by Douglas Hanahan, PhD, of the Swiss Institute for Experimental Cancer Research in Lausanne, showed in a third paper that breast cancer cells that had spread to the brain express their own glutamate receptors of the NMDA subtype (Nature 2019;573:526–31).

Through these receptors, Hanahan's team reported, the cancer cells tap into existing neuronal junctions and feed off glutamate to boost their growth. “It's like they are parasitizing the neurons and synapses,” says Hubert Hondermarck, PhD, a cancer neurobiologist from the University of Newcastle in Callaghan, Australia, who was not involved in the research.

The new studies highlight the possibility of developing drugs that disconnect neuronal linkups. To that end, Winkler cofounded Divide & Conquer in September. The company is focused on developing therapies that disrupt cellular communication networks to combat glioblastoma and other cancers.

Meanwhile, Monje is planning an academic trial that builds on her team's 2017 paper, which showed in xenograft mouse models of high-grade gliomas that pharmacologically blocking the release of neuron-secreted neuroligin-3 into the tumor microenvironment led to cancer growth inhibition (Nature 2017;549:533–7).

Avoiding toxicities may prove challenging because the ties that bind neurons and cancer cells rely on many of the same molecular players as those that unite healthy neurons. “If we start to drug those receptors or those neurotransmitters, we will probably impact the normal functioning of the brain,” Hondermarck says. “At this stage, it's unclear how these findings are going to translate into therapeutic applications, but this is very promising.” –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.