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Cellular hierarchies of ETMR are shaped by oncogenic miRNAs and receptor-ligand interactions

ABSTRACT: Cellular hierarchies of ETMR are shaped by oncogenic miRNAs and receptor-ligand interactions

PROVIDER: PRJNA967009 | ENA |

REPOSITORIES: ENA

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Cellular hierarchies of ETMR are shaped by oncogenic miRNAs and receptor-ligand interactions

Project description:Embryonal tumor with multilayered rosettes (ETMR) is a malignant pediatric brain tumor with a dismal prognosis. The proposed oncogenic driver is amplification and fusion of the chromosome 19 miRNA cluster (C19MC). However, the ramifications of this distinct genetic event as well as the complex tumor architecture and the interactions between malignant cell types in ETMR remain vastly understudied. Here, we have analyzed a cohort of 11 ETMR patients using single-cell transcriptomic and multiplexed spatial protein profiling. We reveal a common, spatially distinct cellular hierarchy, closely resembling normal development presenting as a highly proliferative neural stem cell-like population that gives rise to neuron-like cells. C19MC, which is predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, indicated by high-resolution miRNA:mRNA analyses. Further, we show that FGF- and NOTCH-signaling, important for cell-cell interactions in ETMR, can be successfully targeted in preclinical ETMR models and ETMR patients. Taken together, our study provides unprecedented new insights into fundamental ETMR biology and a powerful rationale for more effective targeted therapies.

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Genome wide methylation profliling of ETMR tumours.

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Genome wide methylation profliling of ETMR tumours.

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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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