Figure S1 shows MYC driven tumors generated from early postnatal cerebellar cells. Figure S2 shows IHC staining of tdt+ or tdt- MYC-driven tumors. Figure S3 shows gene expression of mouse MYC-driven tumors compared to that of human medulloblastomas. Figure S4 shows properties of Sox2+/Aldh1L1high, Sox2+/Aldh1L1low and Sox2+/Aldh1L1neg cells. Figure S5 shows properties of Sox2+/CD133+, Sox2+/CD133- or Sox2-/CD133+ cells. Figure S6 shows gene expression of SOX family members in tumors or normal cerebellar cells. Figure S7 shows that LDHA is a potential target for treating human MYC-amplified medulloblastoma.
ARTICLE 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.
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.
