<i>MYC</i> Drives Group 3 Medulloblastoma through Transformation of Sox2⁺ Astrocyte Progenitor Cells.

Abstract

A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of <i>MYC</i> lacking additional focal aberrations, yet it remains unclear whether <i>MYC</i> 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 <i>MYC</i>. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of <i>MYC</i>-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (<i>LDHA</i>). <i>LDHA</i> abundance correlated positively with <i>MYC</i> expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human <i>MYC</i>-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 <i>MYC</i> and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified <i>LDHA</i> as a novel, specific therapeutic target for this devastating disease. SIGNIFICANCE: Insights from a new model identified <i>LDHA</i> as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.