Spatiotemporal Role of GLI2 in Driving SHH-Medulloblastoma Tumorigenesis

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.