MODL-21. INVESTIGATING THE PATHOGENIC MECHANISMS OF FOXR2-MUTATED PEDIATRIC BRAIN TUMOR USING A HUMAN-EMBRYONIC STEM CELL-BASED MODEL

Abstract

Abstract FOXR2-activated CNS neuroblastoma is a recently identified subtype of brain tumor characterized by genomic rearrangements at the FOXR2 locus and elevated expression of the transcription factor FOXR2. However, the precise mechanisms underlying the tumorigenesis of this specific subtype, including the cell type of origin, are not fully understood. In this study, we established a new tumor model using human embryonic stem cells (hESCs) to determine the cell type of origin and the underlying pathogenic mechanisms. Expression profile analysis of patient tumors revealed increased expression of interneuronal marker genes, such as DLX1, NKX2.1, and SST (Somatostatin). Given that NKX2.1 and SST are markers for interneuronal cells originating from the Medial Ganglionic Eminence (MGE) in the ventral forebrain, we hypothesized that MGE-derived interneuronal progenitors are the cell type of origin. To test this hypothesis, we differentiated hESCs into MGE-type interneuronal progenitors using a chemically defined protocol, while using cortical excitatory neural progenitors as a control cell type. Subsequently, we overexpressed FOXR2 in these cell populations and analyzed the cellular phenotype. Our data showed that, in low density culture, FOXR2 overexpression in the MGE-type interneuronal progenitors led to a significantly greater increase in proliferation compared to the cortical progenitor cells, indicating a cell-type-specific effect of FOXR2. Our novel model holds great promise for elucidating the molecular mechanisms underlying the formation of FOXR2-activated CNS neuroblastoma and paving the way for the discovery of therapeutic targets and effective treatments for patients suffering from this devastating disease.