Human cerebral organoids model tumor infiltration and migration supported by astrocytes in an autologous setting

Efforts to achieve precise and efficient tumor targeting of highly malignant brain tumors are constrained by the dearth of appropriate models to study the effects and potential side effects of radiation, chemotherapy, and immunotherapy on the most complex human organ, the brain. We established a cerebral organoid model of brain tumorigenesis in an autologous setting by overexpressing c-MYC as one of the most common oncogenes in brain tumors. GFP ⁺ /c-MYC ^high cells were isolated from tumor organoids and used in two different culture approaches: assembloids comprising of a normal cerebral organoid with a GFP ⁺ /c-MYC ^high tumor sphere and co-culture of cerebral organoid slices at air-liquid interface with GFP ⁺ /c-MYC ^high cells. GFP ⁺ /c-MYC ^high cells used in both approaches exhibited tumor-like properties, including overexpression of the c-MYC oncogene, high proliferative and invasive potential, and an immature phenotype as evidenced by increased expression of Ki-67, VIM, and CD133. Organoids and organoid slices served as suitable scaffolds for infiltrating tumor-like cells. Using our highly reproducible and powerful model system that allows long-term culture, we demonstrated that the migratory and infiltrative potential of tumor-like cells is shaped by the environment in which glia cells provide support to tumor-like cells.