Brain tumors are the leading cause of cancer-related deaths in children. Tailored therapies need preclinical brain tumor models representing a wide range of molecular subtypes. However, there is a lack of reliable brain tumor cell sources. To address this gap, we developed a bioen-gineered model system that can reconstitute patient cells into a brain-like tumor microenviron-ment, using silk scaffolds infused with extracellular matrix (ECM) gels. A previous study showed that normal human brain cells from patients can only regenerate endogenous neural stem/progenitor cells in long-term cultures. Here, the modeling process was adapted to the dif-ferent stages of tumor spheroid formation and interaction with the extracellular matrix (ECM). Pediatric patient brain tumor cells showed in vitro 3D growth for all major types, including me-dulloblastoma, ependymoma, glioblastoma, and the difficult-to-culture low-grade glioma (e.g., pilocytic astrocytoma). Comparison of 3D formats without gel or with collagen or Matrigel demonstrated the role of the 3D scaffold in supporting diverse cell phenotypes and accommo-dating tumor types of varying spheroid-forming ability. Comparison of the transcriptome pro-files of 3D tumor models and their patient-matched tumor identified the models that best pre-served the gene signatures of the original tumor tissue, such as the medulloblastoma model in a 3D scaffold-only format. Together, these data defined the starting conditions to support a wide range of primary brain tumor types. Our finding also identified genes underlying the differences between the in vitro model and the primary tissue providing mechanistic insights into the tumor microenvironment. This study provides the first step towards establishing a pipeline from patient cells to models to personalized drug testing for brain cancer.