Glioblastoma cells imitate neuronal excitability in humans

Abstract

SummaryGlioblastomas (GBM) are renowned for their pronounced intratumoral heterogeneity, characterized by a diverse array of plastic cell types, which poses a significant challenge to effective targeting and treatment [1]. Recent research has documented the presence of neuronal-progenitor-like transcriptomic cell states of GBM [2, 3], notably in the leading edge of the tumor, where synaptic input from adjacent neurons drives disease proliferation [4]. However, conflicting observations regarding GBM cell excitability, ranging from non-excitable [5] to neuron-like excitability [6], add complexity to our comprehension of the pathophysiological diversity of GBM cells. Here we established a novel experimental workflow enabling comprehensive and selective investigation of the electrophysiological characteristics of cancer cells and neurons within cancer-infiltrated organotypic tissue specimens from GBM patients, using viral genetic labelling to target cellular subtypes. We observed that GBM cells exhibit distinct electrophysiological features in humans, characterized by hyperexcitability and neuron-like action potential generation. Our research provides direct evidence of excitability and a comprehensive description of the electrophysiological characteristics of GBM cells in the cancer-infiltrated cortex of humans, contributing to a deeper understanding of the cellular biology of GBM. These insights have broader implications for understanding cell-cell interactions in malignant tumors and could inform targeted therapies across diverse cancer types, offering a new lens for tackling tumor heterogeneity.