Functional 3D Human Neuron–Glioblastoma Model Reveals Cellular Interactions Enabling Drug Safety Assessments

Glioblastoma (GB) cells actively interact with the central nervous system (CNS) tumor microenvironment (TME). These interactions, particularly with neurons, require a better understanding. 3D tumor models replicating the human TME are needed to unravel pathological processes and to test novel treatments for efficacy and safety. We developed a novel 3D human coculture model for studying neuron–GB interactions. The model revealed both structural and functional interactions between cell types. Paracrine communication in the coculture model favored a tumor-supportive environment. Notably, cell-specific calcium signaling characteristics differed in cocultures compared to monocultures, highlighting the impact of interactions on cellular functionality in TME. The safety of a clinically used treatment, temozolomide, was tested in the 3D coculture model, and it selectively inhibited GB invasion while preserving neurons' morphology and functionality. The established model provides a tool for dissecting the interactions within the TME and testing the efficacy and safety of novel treatments.