Spatiotemporal Role of GLI2 in Driving SHH-Medulloblastoma Tumorigenesis

Medulloblastoma (MB) is a malignant cerebellar tumor primarily affecting children. SHH MB with GLI2 amplification is associated with a particularly poor prognosis. Although GLI2 amplification is clinically recognized, its role in driving SHH-MB remains unclear. We generated novel mouse models of GLI2-amplified MB to investigate the role of GLI2 in driving tumorigenesis and assessed their similarity to human tumors using immunohistological and scRNA-seq analyses. Additionally, we examined the spatiotemporal window of tumor development using our mouse models and explored the mechanisms underlying the susceptibility of embryonic cerebellar granule cell progenitors (GCPs) to GLI2-induced tumorigenesis through scRNA-seq analysis. We further investigated the involvement of MAPK pathway in GLI2-driven tumorigenesis and progression by genetically disrupting the pathway. We demonstrate that GLI2 is a primary oncogenic driver in SHH-MB, with its overexpression driving embryonic Math1+ progenitor cells to form SHH-MB. The resulting GLI2-driven tumors closely resemble human GLI2-amplified SHH-MB cellularly and molecularly. Additionally, we determined that embryonic Math1+ GCPs at E13.5–E15.5 are the most susceptible to tumor initiation with GLI2 overexpression alone. In postnatal Math1+ GCPs, additional Trp53 inactivation is required for GLI2-induced tumor formation. scRNA-seq analysis reveals MAPK pathway enrichment in embryonic GCPs and GLI2-driven tumors. Functional studies show that knocking down MEK1/2 in Math1+ progenitor cells or GLI2-driven MB cells prevents tumorigenesis and tumor progression, respectively. Our studies uncover the developmental origins and molecular mechanisms underlying GLI2-amplified SHH-MB. We also reveal that the MAPK pathway plays a critical role in GLI2-driven SHH-MB tumorigenesis and progression.