Project description:Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric brain tumours driven in most cases by amplification of the chromosome 19 microRNA cluster (C19MC), which upregulates the oncogene MYCN. Whether MYCN dysregulation alone is sufficient to produce ETMR-like tumours, independent of the broader C19MC machinery, has not been tested. Here, we show that sustained MYCN expression in human neuroepithelial stem (NES) cells, i.e. primitive neural progenitors resembling the proposed cell of origin of ETMR, is sufficient to generate ETMR-like brain tumours in vivo. These tumours share methylation and transcriptional signatures with ETMR and reproduce its primitive, stem-like cellular hierarchy. MYCN-expressing tumour cells are arrested at an early neural progenitor stage, and MYCN withdrawal arrests growth and engages neuronal differentiation. Our findings identify sustained MYCN as sufficient to drive an ETMR-like developmental arrest in primitive human neural cells.
Project description:Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric brain tumours driven in most cases by amplification of the chromosome 19 microRNA cluster (C19MC), which upregulates the oncogene MYCN. Whether MYCN dysregulation alone is sufficient to produce ETMR-like tumours, independent of the broader C19MC machinery, has not been tested. Here, we show that sustained MYCN expression in human neuroepithelial stem (NES) cells, i.e. primitive neural progenitors resembling the proposed cell of origin of ETMR, is sufficient to generate ETMR-like brain tumours in vivo. NanoString nCounter miRNA profiling was used to assess microRNA expression in this MYCN-only model, which lacks C19MC amplification.
Project description:Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric brain tumours driven in most cases by amplification of the chromosome 19 microRNA cluster (C19MC), which upregulates the oncogene MYCN. Whether MYCN dysregulation alone is sufficient to produce ETMR-like tumours, independent of the broader C19MC machinery, has not been tested. Here, we show that sustained MYCN expression in human neuroepithelial stem (NES) cells, i.e. primitive neural progenitors resembling the proposed cell of origin of ETMR, is sufficient to generate ETMR-like brain tumours in vivo. These tumours share methylation and transcriptional signatures with ETMR and reproduce its primitive, stem-like cellular hierarchy. MYCN-expressing tumour cells are arrested at an early neural progenitor stage, and MYCN withdrawal arrests growth and engages neuronal differentiation. Our findings identify sustained MYCN as sufficient to drive an ETMR-like developmental arrest in primitive human neural cells.
