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MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS

Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully...

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Autores principales: Luo, Zaili, Lu, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260031/
http://dx.doi.org/10.1093/neuonc/noad073.238
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author Luo, Zaili
Lu, Richard
author_facet Luo, Zaili
Lu, Richard
author_sort Luo, Zaili
collection PubMed
description Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
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spelling pubmed-102600312023-06-13 MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS Luo, Zaili Lu, Richard Neuro Oncol Final Category: Medulloblastomas - MDB Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities. Oxford University Press 2023-06-12 /pmc/articles/PMC10260031/ http://dx.doi.org/10.1093/neuonc/noad073.238 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Final Category: Medulloblastomas - MDB
Luo, Zaili
Lu, Richard
MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
title MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
title_full MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
title_fullStr MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
title_full_unstemmed MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
title_short MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
title_sort mdb-05. human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis
topic Final Category: Medulloblastomas - MDB
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260031/
http://dx.doi.org/10.1093/neuonc/noad073.238
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