Medulloblastoma, the most prevalent brain tumor among children, requires a comprehensive understanding of its cellular characteristics for effective research and treatment. In this study, we focused on DAOY, a permanent cell line of medulloblastoma, and investigated the unique properties of DAOY cells when cultured as floating multicellular aggregates called spheres, as opposed to adherent monolayers. Through our comprehensive analysis, we identified distinct characteristics associated with DAOY spheres. Our findings demonstrate that DAOY spheres express markers for both neural stem cells, such as CD133 (PROM1), and differentiated neurons, exemplified by MAP2. Additionally, our investigation revealed that spheres-derived cells exhibit heightened resistance to ionizing radiation compared to adherent cells. Consequently, our results indicate that caution is advised when interpreting experimental results obtained from adherent cell cultures and extrapolating them to in vivo situations.

• Publication type
• Journal Article MeSH

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

• MeSH
• Ki-67 Antigen metabolism   MeSH
• Cell Differentiation * genetics   MeSH
• Cell Lineage MeSH
• Histone Demethylases MeSH
• Humans MeSH
• Medulloblastoma * classification   genetics   pathology   MeSH
• Metencephalon * embryology   pathology   MeSH
• Cerebellum embryology   pathology   MeSH
• Mutation MeSH
• Cerebellar Neoplasms * classification   genetics   pathology   MeSH
• Hedgehog Proteins metabolism   MeSH
• T-Box Domain Proteins metabolism   MeSH
• Repressor Proteins MeSH
• Muscle Proteins MeSH
• Otx Transcription Factors deficiency   genetics   MeSH
• Core Binding Factor alpha Subunits genetics   MeSH
• Transcription Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Ki-67 Antigen MeSH
• CBFA2T2 myeloid-transforming gene-related protein MeSH Browser
• CBFA2T3 protein, human MeSH Browser
• core binding factor alpha MeSH Browser
• EOMES protein, human MeSH Browser
• Histone Demethylases MeSH
• KDM6A protein, human MeSH Browser
• OTX2 protein, human MeSH Browser
• PRDM6 protein, human MeSH Browser
• Hedgehog Proteins MeSH
• T-Box Domain Proteins MeSH
• Repressor Proteins MeSH
• Muscle Proteins MeSH
• Otx Transcription Factors MeSH
• Core Binding Factor alpha Subunits MeSH
• Transcription Factors MeSH