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Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Recently we identify GNAS, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Furthermore, we identify a population of Olig2-expressing progenitor cells are the major source of tumor-propagating cells. Deletion of Olig2 leads to a delay of tumor progression. Eliminating the mitotic Olig2-expression inhibits tumor initiation. Thus, our present studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, and reveal that Olig2-expressing progenitors are the critical cell origin of G-protein-mediated SHH subgroup medulloblastoma, illuminating potential therapeutic avenues for SHH medulloblastoma by targeting G-protein and Olig2-expressing glial progenitors.

MB-33 * THE CRITICAL ROLE OF OLIG2-EXPRESSING PROGENITORS IN THE INITIATION OF G-PROTEIN MEDIATED SONIC HEDGEHOG-DRIVEN MEDULLOBLASTOMA