Abstract
Progression and infiltration of glioma are induced by neuronal populations remote to the primary tumor.
Major Finding: Progression and infiltration of glioma are induced by neuronal populations remote to the primary tumor.
Concept: SEMA4F promotes synaptic remodeling to induce glioma progression and activity-dependent infiltration.
Impact: This study reveals that glioma–neuron interactions that can alter tumor growth are widespread.
Glioblastoma (GBM) is characterized by high rates of proliferation and infiltration into surrounding brain tissue. Previous studies have indicated that these processes can be influenced through bidirectional signaling between tumor cells and neurons, but the identity of the neuronal subtypes and tumor cell subpopulations that contribute to this phenotype are not well understood. To determine the molecular mechanisms behind the effects of neuronal activity on GBM infiltration and progression as well as the neuronal subtypes that participate in this process, Huang-Hobbs and colleagues used a mouse model that allows for the remote stimulation of neurons and showed that stimulation of neuronal activity in the contralateral hemisphere of the brain to the primary tumor accelerates GBM tumor cell infiltration across hemispheres. Callosal projection neurons were determined to drive this glioma neuronal activity-dependent infiltration and tumor progression. Additional investigation into the cellular and molecular properties of infiltrating glioma cells in the presence of contralateral neuronal stimulation using single-cell RNA sequencing indicated that increased neuronal activity significantly altered the immune microenvironment as well as the cellular constituency of the tumor, with an enrichment in genes associated with glutamatergic synapses and axon guidance being observed. Moreover, spatial transcriptomics revealed that cells with this enriched gene signature are localized to infiltrating tumor cells contralateral to the primary tumor and cells at the leading edge demonstrate enrichment of axon guidance–associated genes. This leading-edge infiltrating gene signature was also confirmed in human GBM. Further studies that evaluated specific axon guidance genes that contribute to glioma progression demonstrated that SEMA4F loss of function impairs infiltration and extends mouse survival, while gain of SEMA4F function accelerates infiltration and reduces overall survival through its ectodomain, suggesting this process occurs through interactions with the microenvironment. Brain hyperactivity was also boosted by SEMA4F through synaptic remodeling. In summary, this study shows that remote neuronal activation induces gene expression changes in gliomas that drive infiltration and progression, suggesting that widespread glioma–neuron interactions are able to alter tumor growth.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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