CALM-GBM: Circuit control by Astrocytes Located in Microenvironment of Glioblastoma

Glioblastoma (GBM) is the most aggressive form of brain cancer. First-line treatment is surgical removal of the tumor but although the tumor core can be successfully excised, invasive GBM cells extending beyond surgical margins persist, leading to recurrence and ultimately death. Recent studies show that these invasive GBM cells can form synaptic connections with nearby healthy neurons. These connections, known as neuroglioma synapses (NGS), create electrical coupling which promotes tumor progression. In healthy brain, 90% of synapses are encapsulated by astrocytes through astroglial coverage, forming a tripartite synapse. However, it is unknown if NGS are similarly ensheathed by astrocytes. In presence of GBM, astrocytes enter a reactive state and are defined as Tumor-Associated Astrocytes (TAAs). Evidence suggests that TAAs connect to invasive GBM cells via gap junctions, enabling calcium signal transfer. However, the role of TAAs in GBM progression through a calcium network and at the NGS remains poorly understood. This proposal aims to: 1. Quantify astroglial coverage of NGS in human GBM samples and a mouse model 2. Measure calcium dynamics between GBM and TAAs to understand how TAAs promote tumor growth. This research will pioneer new directions in cancer neuroscience by identifying the role of TAAs in GBM progression and potentially guiding the development of targeted therapeutic strategies aimed at disrupting these supportive networks.