TY - JOUR
T1 - MYC drives group 3 medulloblastoma through transformation of Sox2 þ astrocyte progenitor cells
AU - Tao, Ran
AU - Murad, Najiba
AU - Xu, Zhenhua
AU - Zhang, Peng
AU - Okonechnikov, Konstantin
AU - Kool, Marcel
AU - Rivero-Hinojosa, Samuel
AU - Lazarski, Christopher
AU - Zheng, Pan
AU - Liu, Yang
AU - Eberhart, Charles G.
AU - Rood, Brian R.
AU - Packer, Roger
AU - Pei, Yanxin
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - 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. Significance: Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
AB - 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. Significance: Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
UR - http://www.scopus.com/inward/record.url?scp=85064466424&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-1787
DO - 10.1158/0008-5472.CAN-18-1787
M3 - Article
C2 - 30862721
AN - SCOPUS:85064466424
SN - 0008-5472
VL - 79
SP - 1967
EP - 1980
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -