MDB-99. SPATIAL AND TEMPORAL DEVELOPMENT OF GLI2-DRIVEN MEDULLOBLASTOMA

Abstract

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant tumor of the cerebellum predominantly affecting children. It can be classified into four major molecular subgroups: WNT, SHH, Group 3, and Group 4. Among these subgroups, the SHH subgroup MB, characterized by GLI2 amplification, is associated with a poor prognosis. However, while GLI2 alterations have been linked to SHH-MB, evidence demonstrating its role as an oncogenic driver in an animal model is lacking. Understanding the mechanisms underlying GLI2-amplified MB initiation and progression is crucial for developing improved therapeutic strategies. METHODS By utilizing transgenic mouse models, our study aims to elucidate the role of GLI2 in SHH-MB tumorigenesis and uncover the underlying mechanisms driving tumor formation. This research effort seeks to identify novel therapeutic targets for the treatment of this disease. RESULTS We discovered that overexpression of GLI2 in embryonic Math1+ granule neuron precursors (GNPs) led to tumorigenesis within the cerebellum, resulting in 100% mortality in the mice. Importantly, the cellular and molecular characteristics of these tumors faithfully recapitulated those found in human SHH-MB. Further analysis revealed that only Math1+ GNPs specifically between E13.5 and E15.5 are susceptible to GLI2-induced tumorigenesis, while overexpression of GLI2 in embryonic GFAP+ stem cell/progenitors failed to induce tumorigenesis. Additionally, our single-cell RNA-seq analysis unveiled the heterogeneity of Math1+ cells during cerebellar development. Furthermore, we demonstrated that the MAPK signaling pathway was involved in the tumorigenesis of embryonic Math1+ GNPs by preventing cell apoptosis. CONCLUSIONS Our findings establish a pivotal oncogenic role of GLI2 in SHH-MB tumorigenesis, with GLI2-driven tumors developing within a specific spatial-temporal window from a distinct cell population during cerebellar development. Targeting the MAPK signaling pathway holds promise in preventing tumorigenesis and progression of GLI2-amplified MB.