Retinoid-Induced Neuronal Differentiation and Apoptosis of Medulloblastoma
This project aims to define the pathways critical for neuronal differentiation and apoptosis of medulloblastoma cells. Medulloblastomas are a group of primitive neuro-ectodermal tumors that are able to maintain an undifferentiated phenotype while over expressing some genes that are responsible for neuronal differentiation. Retinoic acid receptors have been identified in most medulloblastoma samples and it is possible that retinoic acid antagonists will be useful therapeutically in medulloblastoma, In pilot experiments, we have shown that all-trans retinoic acid and several specific retinoid agonists induce neural differentiation and apoptosis of the medulloblastoma cell line D283 Med. Preliminary experiments showed the Notch ligand, Jagged1, was down-regulated with all the retinoic acid agonists tested. A decrease in inhibitory signals from the Jagged/Notch pathway may thus make medulloblastoma permissive to a neural differentiation program.
This collaborative study has three specific aims. First, to correlate gene expression changes in response to four retinoic acid agonists in three medulloblastoma cell lines with the phenotypic changes of neural differentiation and apoptosis. Second, to assess if downregulation of the Jagged/Notch1 pathway is necessary or sufficient for neuronal differentiation of medulloblastoma cells. Finally, the mechanisms of apoptosis of medulloblastoma cells in response to retinoids will be defined. This will characterize the modes of action of retinoids in medulloblastoma and provide a model to screen other agents for biologic efficacy in treatment of this tumor.