Researchers at the Baylor College of Medicine working with animal models have described a process by which neurons in locations remote to the primary tumor provoke expression of gene from glioblastoma (GBM) that drive tumor infiltration. The findings, published this week in Nature, help explain why GBM recurrence is inevitable and usually occurs outside the surgical margins of the primary tumor.
“Previous studies have shown associations between the presence of GBM and increased neuronal activity in surrounding brain regions, which can promote tumor progression,” said first author Emmet Huang-Hobbs, PhD, who works I the lab of Benjamin Deneen, PhD.
In their work, the Baylor researchers sought to find the mechanisms of how neurons stimulate GBM infiltration. They first determined which populations of neurons are active in spurring glioma intrusion and hypothesized that callosal projection neurons (CPNs) localized in the cortical hemispheres contralateral to the primary tumor contributed to this activity. CPNs stretch across the corpus callosum as a strip of white matter that connects the brain’s two hemispheres.
“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.
According to Dineen, the new findings point to glioblastomas receiving neuronal inputs from many different regions in the brain, and that exposure to a variety of neuroactive compounds may influence the spread of GMB and tumor growth and that tumor-neuron interactions are much more widespread than previously thought.
The research also tapped the research groups of Jeffrey L. Noebels, MD, PhD, and Ganesh Rao. MD, which showed that GBM and CPNs “have a two-way conversation,” Huang-Hobbs noted. “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.”
Following this finding, the investigators were also able to uncover some of the mechanics behind the communication between GBM and CPNs. The team discovered that the infiltrating tumor population is enriched for axon guidance genes including SEMA4F, which was determined to be and essential factor for GMB progression and neuronal activity-dependent infiltration.
“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-Hobbs concluded. “A better understanding of the two-way conversation between GBM and CPNs is an important step toward improved brain tumor treatments.”
