Abstract Neurofibromatosis type 1 (NF1) is a genetic disorder caused by NF1 gene mutations, affecting 1 in 3,000 individuals globally and characterized by cutaneous neurofibromas and an elevated tumor risk, with 15–20% of patients developing gliomas. While NF1 inactivation is associated with low-grade gliomas, the drivers of malignant transformation remain poorly understood. We hypothesize that a permissive NF1-mutant cerebral microenvironment may contribute to glioma transformation and treatment responses. Current preclinical models, such as glioma cell lines and xenografts, fail to replicate the complex NF1 tumor microenvironment. Human induced pluripotent stem cell (hiPSC)-derived cerebral organoids offer a promising platform for studying NF1-driven neurodevelopment and tumor biology. This study investigates the role of NF1 mutations in cerebral organoid development, glioma plasticity, and treatment response. Cerebral organoids were generated from healthy control and NF1-mutated (NF1+/-, NF1-/-) iPSCs reprogrammed from plexiform neurofibromas. Organoids were analyzed for cytoarchitectural development at key stages using immunofluorescence. mCherry-labeled glioma cells were co-cultured with cerebral organoids to assess glioma migration (qualitative imaging), proliferation (qPCR), secretome profiles (MSD), and treatment responses. Initial immunofluorescence data showed no significant differences in neuronal development between wild-type and NF1-mutant organoids. However, preliminary co-culture experiments indicated increased glioma migration and proliferation in NF1-mutant organoids compared to healthy controls. Elevated levels of GM-CSF and IL-18, cytokines implicated in glioma growth and invasion, were detected in the secretome of NF1-mutant organoid-glioma co-cultures. These findings suggest that NF1 mutations foster a tumor-supportive microenvironment, enhancing glioma aggressiveness. This study highlights the utility of NF1-mutant organoids as a model to investigate glioma behavior and NF1-associated tumor predisposition. Future analyses, including single-cell RNA sequencing and spatial transcriptomics, will validate the role of NF1 in glioma progression and support ex vivo drug testing to advance personalized therapies for NF1-driven gliomas.
Chatterjee et al. (2025) studied this question.