Remodeling Group 3 medulloblastoma: MYC overexpression alone transforms progenitors of astrocytes and granule neurons in the postnatal cerebellum

Group 3 medulloblastoma is often associated with MYC amplification or overexpression, while whether MYC overexpression alone is sufficient to induce tumorigenesis is unknown and the cell type(s) which can be transformed by MYC is unclear. Here, by generating a new mouse model, we demonstrated that overexpression of Myc alone is sufficient to transform astrocyte progenitors and granule neuron progenitors (GNP) in the early postnatal cerebellum following orthotopic transplantation. The resulting tumors resemble human Group 3 medulloblastoma in terms of both histology and gene expression profiles. Using these models we found that inhibition of lactate dehydrogenase A (LDHA) significantly reduced both murine and human MYC-driven tumor growth, but did not affect SHH medulloblastoma, indicating that LDHA is potential and specific therapeutic target for MYC-driven medulloblastoma. Overall design: We generated tumors from Sox2+ or Math1+ cells in the postnatal cerebellum. Sox2+ or Math1+ cells were purified by FACS sorting from cerebella of P5-P6 Sox2-GFP or Math1-GFP mice. The cells were then infected with Myc lentivirus, cultured for 16 hr and injected into the cerebella of immunodeficient mice. Animals were sacrificed when they developed symptoms of brain tumors. The resulting tumors generated from Sox2+ or Math1+ cells were named SOX2 tumors or MATH1 tumors. Tumor cells, Sox2+ and Math1+ normal cerebellar cells were used for RNA isolation, subsequent cDNA libraries construction and RNA-sequencing using Illumina HiSeq 4000.