Glioblastoma (GBM) is among the most malignant and lethal brain cancers. It is notoriously difficult to treat and carries a poor prognosis. Current treatment protocols combine a highly invasive surgical resection, Tumor Treating Fields, radiotherapy and chemotherapy with temozolomide, yielding a median survival of less than 2 years. A major barrier in the quest for better therapies is the invasive nature of GBM cells, which helps them infiltrate surrounding brain parenchyma, and the pronounced heterogeneity of the tumor microenvironment. The absence of preclinical models that reflect the tumor’s complex microenvironment. especially the role of microglia, the brain’s resident immune cells, also have contributed
In a new study published in Scientific Reports, researchers used advanced 3D “humanized” tumor spheroids, to explore how microglia influence GBM behavior. They built homotypic spheroids (containing only glioma cells) and heterotypic spheroids (combining glioma cells with microglia). The glioma models were derived from a GBM cell line (DK-MG) and patient-derived glioma stem cells (GB22-13).
The authors found that tumors grown with microglia were more aggressive than those without. Heterotypic spheroids grew larger, proliferated faster, and became significantly more resistant to temozolomide. Within 7 days, these tumors developed multinucleated structures and showed greater invasive potential (features associated with more advanced and hard-to-treat disease).
The mixed-cell spheroids developed a distinct “core-shell” architecture. Glioma cells clustered in the center, while microglia formed a surrounding outer layer. This protective shell appeared to limit chemotherapy penetration into the tumor core, potentially explaining the increased drug resistance observed in these models.
Microglia promoted immune evasion. Heterotypic spheroids induced migration and polarization of peripheral blood monocytes (THP-1 cells) toward an M2-like phenotype, a state linked to tumor-supportive, anti-inflammatory immune responses.
This model is a unique approach that can be used for drug screening and the study of glioma-glia interactions. Further research is needed to validate the results and explore how the model applies to similar tumors.