Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation

Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating syn-apse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.

Automated summary

Seizures are a common feature of malignant glioma and recent studies have found that peritumoral synaptic dysregulation plays a role in brain hyperactivity and tumor progression. Through single-cell RNA sequencing and patient ECoG recordings, this study shows that seizure patients have enriched gene signatures related to synapse formation in their tumors. The gene IGSF3 is identified as a mediator of glioma progression and dysregulated neural circuitry, leading to spreading depolarization. Further investigation reveals that IGSF3 interacts with Kir4.1 to suppress potassium buffering and seizure patients have reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging confirms that dysregulated synaptic activity originates from the tumor-neuron interface, validating findings in patients. This study highlights the importance of ion dyshomeostasis in tumor progression and seizures.