Remote neuronal activity drives glioma progression through SEMA4F

Area of Science:

• Neuro-oncology
• Cancer Biology
• Molecular Neuroscience

Background:

• The tumor microenvironment is crucial in cancer progression, with neurons increasingly recognized as key players promoting tumorigenesis.
• Glioblastoma (GBM) exhibits bidirectional signaling with neurons, creating a cycle of proliferation and brain hyperactivity, but specific cell types involved remain unclear.

Purpose of the Study:

• To identify specific neuronal and tumor subpopulations driving GBM progression and infiltration.
• To elucidate the molecular mechanisms underlying neuron-glioma interactions and their impact on tumor behavior.

Main Methods:

• Analysis of contralateral callosal projection neurons in GBM models.
• In vivo screening of axon guidance genes in infiltrating tumor cells.
• Assessment of SEMA4F function in tumor progression and neuronal signaling.

Main Results:

• Callosal projection neurons remote from primary GBM tumors were found to promote tumor progression and infiltration.
• An activity-dependent infiltrating tumor cell population, enriched for axon guidance genes, was identified at the tumor's leading edge.
• SEMA4F was identified as a key regulator, promoting tumor infiltration and hyperactivity by remodeling synapses and enhancing bidirectional neuron-tumor signaling.

Conclusions:

• Subsets of neurons distant from primary GBMs can significantly promote malignant progression.
• SEMA4F mediates activity-dependent glioma progression and bidirectional communication with neurons, offering potential therapeutic targets.