Electrophysiology of glioma: a Rho GTPase-activating protein reduces tumor growth and spares neuron structure and function

BACKGROUND: Glioblastomas are the most aggressive type of brain tumor. A successful treatment should aim at halting tumor growth and protecting neuronalcells to prevent functional deficits and cognitive deterioration. Here, weexploited a Rho GTPase-activating bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), to interfere with glioma cell growth in vitro and vivo. We also investigated whether this toxin spares neuron structure and function inperitumoral areas.METHODS: We performed a microarray transcriptomic and in-depth proteomic analysisto characterize the molecular changes triggered by CNF1 in glioma cells. We also examined tumor cell senescence and growth in vehicle- and CNF1-treatedglioma-bearing mice. Electrophysiological and morphological techniques were used to investigate neuronal alterations in peritumoral cortical areas.RESULTS: Administration of CNF1 triggered molecular and morphological hallmarksof senescence in mouse and human glioma cells in vitro. CNF1 treatment in vivoinduced glioma cell senescence and potently reduced tumor volumes. In peritumoralareas of glioma-bearing mice, neurons showed a shrunken dendritic arbor andsevere functional alterations such as increased spontaneous activity and reduced visual responsiveness. CNF1 treatment enhanced dendritic length and improvedseveral physiological properties of pyramidal neurons, demonstrating functionalpreservation of the cortical network.CONCLUSIONS: Our findings demonstrate that CNF1 reduces glioma volume while atthe same time maintaining the physiological and structural properties ofperitumoral neurons. These data indicate a promising strategy for the developmentof more effective antiglioma therapies.