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MYCN sustains a progenitor-stage differentiation block in human neuroepithelial stem cells to drive ETMR-like tumourigenesis [NanoString miRNA]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339374 | GEO | 2026/07/23

REPOSITORIES: GEO

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MYCN sustains a progenitor-stage differentiation block in human neuroepithelial stem cells to drive ETMR-like tumourigenesis [RNA-seq]

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.

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MYCN sustains a progenitor-stage differentiation block in human neuroepithelial stem cells to drive ETMR-like tumourigenesis [scRNA-seq]

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The Molecular Landscape of ETMR at Diagnosis and Relapse [methylation]

Project description:ETMRs are aggressive pediatric embryonal brain tumors with universally dismal outcome. We collected 193 ETMR samples and an additional 23 matched relapses to investigate the genomic landscape of this distinct entity. We found that patients having tumors without C19MC amplification, the proposed driver, frequently harbor DICER1 germline mutations or other miRNA-related aberrations such as somatic miR-17-92 miRNA cluster amplifications. Despite these distinct genetic aberrations, no molecular subgrouping was observed. Whole-genome sequencing revealed an overall low recurrence of SNVs, but prevalent R-loop-associated chromosomal instability, of which we show that this can be induced by loss of DICER1 function. Comparing primary tumors and matched relapses revealed a strong conservation of SVs but low conservation of SNVs. Moreover, many newly acquired SNVs are associated to a new cisplatin treatment related mutational signature. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

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Genome wide methylation profliling of ETMR tumours.

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A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors

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Gene expression data from ETMR cell line BT183

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Integrated proteomics spotlight the proteasome as a pervasive therapeutic vulnerability in Embryonal Tumors with Multilayered Rosettes (ETMR)

Project description:Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is based on only few previous molecular studies, which mainly relied on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics with the aim to identify novel therapeutic vulnerabilities in these deadly tumors. Using mass spectrometry, proteome data were acquired from FFPE tissue of 40 embryonal brain tumors (16 ETMR, 9 atypical teratoid/rhabdoid tumors (AT/RT), 15 medulloblastomas (MB)) and integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further pediatric brain tumors. Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Microdissection analyses highlighted the close relationship of ETMR histomorphology and proteome profiles, regardless of intra- or intertumoral comparisons. Integrated proteomics showcased that ETMR harbor proteasome regulatory proteins in abundancy, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Respectively, in vitro cell culture viability assays using embryonal brain tumor cell lines BT183 (ETMR), BT16 (AT/RT), and D283 (MB) highlighted that ETMR cells were highly vulnerable towards treatment with the CNS penetrant proteasome inhibitor Marizomib. In summary, histomorphology stipulates the proteome signatures of ETMR. Pervasive and histomorphology-independent abundancy of proteasome regulatory proteins in ETMR indicates a strong proteasome dependency throughout these tumors. As validated in cell culture experiments, proteasome inhibition poses a promising therapeutic option in ETMR.

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