Drives Group 3 Medulloblastoma through Transformation of Sox2 Astrocyte Progenitor Cells.

A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of lacking additional focal aberrations, yet it remains unclear whether overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by . The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of -driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (). abundance correlated positively with expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human -driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified as a novel, specific therapeutic target for this devastating disease. SIGNIFICANCE: Insights from a new model identified as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.