Microenvironment T-Type calcium channels regulate neuronal and glial processes in glioblastoma

Glioblastoma (GBM) is the most primary common malignant brain tumor. The aim of this study was to elucidate the role of intrinsic and microenvironment T-type calcium channels (Cav3) in promoting tumor growth and progression. Cav3.2 KO in the microenvironment led to significant reduction in GBM growth and prolongation of animal. Single-cell RNA sequencing showed that microenvironment Cav3.2 regulates neuronal and glial biological processes. Microenvironmental Cav3.2 downregulated numerous genes associated with regulating OPC cell state such as SOX10 and Olig2. Neuronal Cav3.2 promoted neuron/GSC synaptic connections and GSC growth. Treatment of GSCs with the Cav3 blocker mibefradil downregulated genes associated with neuronal processes. The combination of mibefradil with temozolomide and radiation significantly reduced tumor volume providing an additive effect compared to TMZ/radiation alone. Together these data reveal a role for microenvironmental Cav3 in promoting GBM tumor progression through regulating neuronal and glial processes particularly associated with the OPC-cell state. Targeting both intrinsic and microenvironment Cav3 with mibefradil significantly enhanced the anti-GBM effects of TMZ and radiation. Overall design: WT or Cav3.2KO mice had GBM cells implanted which were harvested at day 24 for single-cell RNA-seq