Glioblastoma (GBM) is a highly aggressive brain tumour, constituting 50% of all primary malignant brain tumours. The median survival time for GBM patients is approximately 15 months, and treatment options are limited. A characteristic feature of GBM is the excessive release of glutamate from astrocytes, which contributes to tumour progression. Currently, temozolomide (TMZ) is the only FDA-approved chemotherapy for GBM, but patients often quickly develop resistance, rendering the drug ineffective. To combat these challenges, our research aims to delve into the mechanistic aspects of aberrant glutamate signalling in GBM and develop new strategies to counteract chemoresistance.

There are reports of Ca2+ dependency of glutamate release from astrocytes majorly influenced by the intracellular stores. However, the Ca2+ mediated vesicle dynamics and its influence on glutamate release in astrocytes is not clearly defined. Therefore, we plan to understand the association of a recently reported endoplasmic reticulum (ER) protein, LRRC8B with glutamate release in astrocytes and GBM cells. LRRC8B is a part of Ca2+ signalling network and is highly expressed in brain. Our results show that LRRC8B affects glutamatergic vesicle dynamics and glutamate release in astrocytes and GBM cells.

Studies have demonstrated that thin tubular extensions of the membrane called tunnelling nanotubes (TNTs) promote TMZ resistance in GBM cells. TNTs enable cell to cell communication and are induced in response to TMZ treatment in GBM cells. This communication allows the passage of drug resistant molecules to sensitive cells conferring them TMZ resistance. Our goal is to overcome TMZ resistance by focusing on targeting TNT. Our initial findings indicate that it is possible to destabilize TNT in GBM by elevating intracellular Ca2+ levels. The drugs elevating intracellular Ca2+ were able to cause TNT retraction. Combining TMZ with the calcium elevating drugs reduced GBM cell growth compared to TMZ alone. Therefore, we aim to study whether this innovative strategy holds promise in preventing the emergence of TMZ resistance and enhancing treatment efficacy.