Human cerebral organoids model tumor initiation and infiltration in an autologous astrocyte-supported setting

Efforts to efficiently target brain tumors are constrained by the dearth of appropriate models to study tumor behavior toward treatment approaches as well as potential side effects to the surrounding normal tissue. We established a reproducible cerebral organoid model of brain tumorigenesis in an autologous setting by overexpressing <i>c-MYC</i>, a common oncogene in brain tumors. GFP⁺/c-MYC^high cells were isolated from tumor organoids and used in two different approaches: GFP⁺/c-MYC^high cells co-cultured with cerebral organoid slices or fused as spheres to whole organoids. GFP⁺/c-MYC^high cells used in both approaches exhibited tumor-like properties, including an immature phenotype and a highly proliferative and invasive potential. We demonstrate that the latter is influenced by astrocytes supporting the GFP⁺/c-MYC^high cells while X-ray irradiation significantly kills and impairs tissue infiltration of GFP⁺/c-MYC^high cells. In summary, the model represents major features of tumorous and adjacent normal tissue and may be used to evaluate appropriate cancer treatments.