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Cancer Res. 2019 Mar 12. pii: canres.1787.2018. doi: 10.1158/0008-5472.CAN-18-1787. [Epub ahead of print]

MYC drives Group 3 medulloblastoma through transformation of Sox2+ astrocyte progenitor cells.

Author information

1
Children's National Health System.
2
Center for Cancer and Immunology, Children's National Health System.
3
School of Medicine, University of Maryland, Baltimore.
4
German Cancer Research Center.
5
Pediatric Neurooncology, German Cancer Research Center.
6
Center for Cancer and Immunology Research, Children's National Health System.
7
Institute of Human Virology, University of Maryland, Baltimore.
8
Institute of Human Virology,, University of Maryland, Baltimore.
9
Pathology,Oncology, Ophthalmology, Johns Hopkins University School of Medicine.
10
Dept of Neurology, Children's National Health System.
11
Cancer and Immunology Department, Brain Tumor Institute, Children's National Health System ypei@cnmc.org.

Abstract

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

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