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.