Modeling pediatric low-grade glioma heterogeneity using human forebrain organoids

Pediatric low-grade gliomas (pLGGs) are the most common type of brain tumors in children, characterized by their typically slow growth and oncogene-induced senescence. Preclinical models provide the opportunity to investigate the effects of various treatments in a controlled setting before they are tested in human patients; however, reliable models for pLGGs are limited. Here we developed two organoid models for pLGGs, which, after engraftment into mice, exhibited low-grade features. Furthermore, the genome-wide DNA methylation and RNA profiles of the organoids demonstrated closer similarity to low-grade glioma entities compared to high-grade counterparts. Additionally, pLGG organoid-derived cells align with oligodendrocyte-like, astrocyte-like and MAPK signature clusters seen in patient tumors, indicating that the organoids generate a heterogeneous population of cancer cells, where cellular diversity may influence disease progression and treatment response.