Article
Electrical signaling is essential for dynamic transcriptional plasticity in Glioblastoma
Elektrische Signalübertragung ist für die dynamische Transkriptionsplastizität bei Glioblastomen von wesentlicher Bedeutung
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Published: | May 25, 2022 |
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Objective: Owing to recent advances in understanding of the active functional states exhibited within glioblastoma (GBM), intra-tumoral cellular signaling has moved into focus of neuro-oncological research. In our study, we aim to explore the role of transcellular electrical signaling and investigate correlations to transcriptional dynamics and cellular behavior.
Methods: Electrophysiological characterization was carried out using 2D planar microelectrodes, in a human neocortical tissue based GBM model. Exposure to conditions such as hypoxia and acidic environment was carried out to identify signaling patterns as a response to specific environmental conditions. Effect of signaling inhibition was transcriptionally characterized by means of scRNA-sequencing with CRISPR based perturbation.
Results: Electrophysiological characterization revealed network activity exhibiting characteristics of scale-free networks. Cellular signaling was directly correlated to changes in the environment, like hypoxia or glutamatergic activation, with modulation of either frequency or amplitude of recorded events encoding information regarding changes in the local microenvironment. CRISPR based perturbation of synapse forming genes resulted in alterations in cellular morphology (p?<?0.001) and decreased cellular connectivity (p?<?0.001), with electrical signaling being significantly attenuated (p?<?0.0001). Single-cell sequencing of perturbed tumor cells in the neocortical GBM model revealed a loss of developmental lineages (FDR<0.01) and significant reduction of cellular stress response state (FDR<0.01).
Conclusion: Our findings highlight the role of electrical signaling in glioblastoma. Cellular stressors induce intercellular signaling, leading to transcriptional adaptation suggesting that there exists a highly complex and powerful mechanism for dynamic transcriptional state adaptation.