Long-Range Neuronal Activity Fuels Brain Tumor Infiltration

Using animal models, researchers at Baylor College of Medicine have discovered a long-range two-way communication process used by neurons that can drive the infiltration of glioblastomas in the brain. The research is published in Nature.

Mechanisms underlying glioblastoma

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor. They account for approximately half of all cancerous tumors that originate in the brain. Despite modern therapies, the median survival for GBM patients is just 15 months.

Invasion and infiltration of these tumors into surrounding tissue play an important role in its aggressiveness. Tumors almost always return despite surgical removal and can even occur some distance away from the original (primary) tumor, though surprisingly little is known about the mechanisms that drive this.

“Previous studies have shown associations between the presence of GBM and increased neuronal activity in surrounding brain regions, which can promote tumor progression,” said Dr. Emmet Huang-Hobbs, lead author of the study.

Long-range projections drive tumor progression

To investigate how increased neural activity may stimulate the spread of GBM, the researchers first needed to identify which neurons were responsible.

They hypothesized that callosal projection neurons (CPNs) – which extend across the brain and span across the corpus callosum, the white matter that connects the brain’s left and right hemispheres – may play a role.

Using mouse models of GBM, the team focused on CPNs located in the cortical hemisphere of the brain, on the other side of the brain to the primary tumor.

“Severing the corpus callosum eliminated the neuronal activity-dependent acceleration of GBM infiltration that was observed with the intact control, supporting that an intact corpus callosum is necessary to promote glioma progression and implicating CPNs’ long-range projections in remotely driving GBM infiltration,” Huang-Hobbs said.

“The findings suggest that GBMs receive neuronal inputs from a host of brain regions, implying that exposure to a diverse range of neuroactive compounds can potentially influence tumor growth. It’s now clear that tumor–neuron interactions are more widespread than previously thought,” said Professor Benjamin Deneen, senior author of the study and professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery at Baylor College of Medicine.

“[…] we found evidence suggesting that GBM and CPNs have a two-way conversation,” Huang-Hobbs said. “CPNs promote tumor infiltration, and the tumor affects neuronal connections or synapses. The tumor remodels local neuronal synapses and makes direct synaptic connections, raising the possibility that it alters brain circuit activity in these regions that are distant from the primary tumor.”

Next, the researchers probed some of the underlying mechanisms involved in these long-range two-way conversations. Cells in the infiltrating tumor population had increased expression of so-called axon guidance genes, which help to direct the growth of neurons. They also identified a gene called semaphorin-4F (SEMA4F) – which promotes brain hyperactivity – as essential for the progression and infiltration of GBMs.

“Taken all together, we propose a model in which neurons prompt the expression of genes from glioma tumors that subsequently drive infiltration and their own synaptic activity,” Huang said. “A better understanding of the two-way conversation between GBM and CPNs is an important step toward improved brain tumor treatments.”

Reference: Huang-Hobbs E, Cheng YT, Ko Y, et al. Remote neuronal activity drives glioma progression through SEMA4F. Nature. 2023:1-7. doi: 10.1038/s41586-023-06267-2

This article is a rework of a press release issued by Baylor College of Medicine. Material has been edited for length and content.