Calcium Signalling in Glioblastoma Networks of Different Topologies and Possible Treatments

Abstract

Glioblastoma cells form connected cell networks, utilizing tumor microtubes to transmit calcium between cells. A new cell type called "periodic cell" is integral in sustaining calcium signalling in a glioblastoma network. Periodic cells are rare, can sustain consistent intracellular calcium transients, are likely to have KCa3.1 pumps, and have on average more tumor microtubes than other glioma cells. Here we adapt an ordinary differential equation model for intracellular as well as intercellular calcium signalling and apply it to a large glioma cell network. Using the model, three main hypotheses for the driving mechanism of periodic cells were tested: 1. a fixed and elevated IP3 concentration, 2. added benefit from influx of calcium due to KCa3.1 pumps, or 3. oscillation in calcium influx into the cell through the plasma membrane. All three hypotheses yield similar calcium oscillation patterns resembling the trends seen in the data of Hausmann et al. 2023. In vivo, glioma networks were shown to have small-world and scale free network properties. We apply our model to small-world, scale-free and random networks. For these networks, we test how communication is inhibited through removal of cells, removal of tumor microtubes, and inhibition of KCa3.1 pumps. All three network types were more vulnerable to random cell damage than to random TM damage. We find that inhibition of KCa3.1 pumps can have a significant impact on the inhibition of network communication, however, to fully degrade the calcium signalling network, all periodic cells must be eradicated, confirming experimental observations.