CSIG-18. CALCIUM COMMUNICATION IN GLIOMA: CRUCIAL PACEMAKER CELLS GOVERN TUMOR PROGRESSION

Abstract

Abstract BACKGROUND Gliomas form therapy-resistant multicellular networks, using neurite-like protrusions (called Tumor Microtubes [TMs]), and display intercellular calcium transients, that drive brain tumor malignancy. METHODS A refined in vitro model was established to study calcium communication and its molecular toolkit in patient-derived glioma cells. In vitro results were then validated with longitudinal in vivo two-photon calcium imaging in awake mice. RESULTS Here we first describe the discovery of a small subpopulation of glioma cells that display intrinsically active calcium oscillations and behave like pacemakers. Accordingly, these pacemaker-like glioma cells trigger synchronized calcium activity in tumor cells that are connected with them via TMs. The application of network theory shows that glioma cell networks follow a scale-free and small-world topology, governed by a subpopulation of highly connected hub cells. Interestingly, the pacemaker cells most often act as these hubs, hence communicating with many other network members. Graph theory predicts that such network design displays a high degree of robustness, making it resistant to random damage as seen after radio- and chemotherapy – but extremely vulnerable to selective damage to key hubs. In line with this theory, laser ablation of the pacemaker-like hub cells splintered the malignant tumor network into small isolated cell clusters and led to increased cell death, whereas laser ablation of random tumor cells showed no effect. Among others, KCNN4 channels, which are upregulated in gliomas, were identified as drivers of the pacemaker-like hub cells. Suppressing their pacemaking-abilities by KCNN4 inhibition strongly reduced calcium communication and tumor growth. CONCLUSION In summary, coordinated calcium communication in glioma drives brain tumor malignancy. A specific tumor cell subpopulation was identified that acts as hubs of the multicellular network and initiates global calcium activity. The network’s vulnerability to loosing these pacemaker-like hub cells suggests a novel targeted approach against the resistant networks of gliomas.