Oncogenic mechanisms underlying GLI2-amplified medulloblastoma - Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. There are several subtypes of MB, and among them, the GLI2-amplified SHH-MB subtype has the worst prognosis and a poor survival rate; the 5- year survival rate is <30%. Moreover, the GLI2-amplified MBs are non-responsive to the only targeted treatment option available for SHH-MB, the SMO inhibitors. This leaves an unmet critical treatment gap, and there is an urgent need to identify novel targets to develop effective therapeutics. However, a deeper understanding of the cellular and molecular mechanisms driving GLI2-amplified MB tumorigenesis is currently lacking. With a focused goal to resolve this particular type of MB tumorigenesis, we recently generated an engineered mouse model of GLI2-driven MB. Using this model, we demonstrated that GLI2 is the critical driver of tumorigenesis and identified granule cell progenitors (GCPs) as the cells of origin. Interestingly, we have also found that GLI2 drives only Math1+ embryonic GCPs but not neonatal GCPs to form SHH-MB. Correspondingly, our scRNA-seq analysis revealed that the MAPK pathway is specifically enriched in embryonic but not neonatal Math1+ GCPs. Moreover, the MAPK pathway is activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor significantly delayed the growth of GLI2-driven MB in vivo. Based on these exciting preliminary data, we put forward a novel hypothesis that GLI2-driven MB originates from a specific cell population of Math1+ GCPs and in a particular spatiotemporal window during cerebellar development. Therefore, targeting MAPK/MEK/ERK pathway in the embryonic GCPs in a specific timeframe can effectively prevent GLI2- driven MB initiation and progression. In this proposal, we plan to use our new GLI2-driven MB transgenic mouse model to define the spatiotemporal window of tumorigenesis of GLI2-driven MB more precisely and establish whether MAPK/MEK/ERK signaling is required for GLI2-driven MB initiation and development. Furthermore, we will use GLI2-amplified MB patient-derived xenograft (PDX) models to evaluate the efficacy of MEK/ERK inhibitors in preventing tumor progression and examine the mechanisms underlying therapeutic resistance. We will pursue our ultimate goal to design novel therapeutics and achieve better treatment outcomes by targeting MAPK/MEK/ERK pathway and via identifying additional combinational therapeutic opportunities to fight against tumor relapse. Since aberrant expression of GLI2 occurs in a number of other tumor types, our studies will also set a precedent for all GLI2-driven malignancies.
