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Mapping pediatric brain tumors to their origins in the developing cerebellum
BACKGROUND: Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tiss...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547518/ https://www.ncbi.nlm.nih.gov/pubmed/37534924 http://dx.doi.org/10.1093/neuonc/noad124 |
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author | Okonechnikov, Konstantin Joshi, Piyush Sepp, Mari Leiss, Kevin Sarropoulos, Ioannis Murat, Florent Sill, Martin Beck, Pengbo Chan, Kenneth Chun-Ho Korshunov, Andrey Sah, Felix Deng, Maximilian Y Sturm, Dominik DeSisto, John Donson, Andrew M Foreman, Nicholas K Green, Adam L Robinson, Giles Orr, Brent A Gao, Qingsong Darrow, Emily Hadley, Jennifer L Northcott, Paul A Gojo, Johannes Kawauchi, Daisuke Hovestadt, Volker Filbin, Mariella G von Deimling, Andreas Zuckermann, Marc Pajtler, Kristian W Kool, Marcel Jones, David T W Jäger, Natalie Kutscher, Lena M Kaessmann, Henrik Pfister, Stefan M |
author_facet | Okonechnikov, Konstantin Joshi, Piyush Sepp, Mari Leiss, Kevin Sarropoulos, Ioannis Murat, Florent Sill, Martin Beck, Pengbo Chan, Kenneth Chun-Ho Korshunov, Andrey Sah, Felix Deng, Maximilian Y Sturm, Dominik DeSisto, John Donson, Andrew M Foreman, Nicholas K Green, Adam L Robinson, Giles Orr, Brent A Gao, Qingsong Darrow, Emily Hadley, Jennifer L Northcott, Paul A Gojo, Johannes Kawauchi, Daisuke Hovestadt, Volker Filbin, Mariella G von Deimling, Andreas Zuckermann, Marc Pajtler, Kristian W Kool, Marcel Jones, David T W Jäger, Natalie Kutscher, Lena M Kaessmann, Henrik Pfister, Stefan M |
author_sort | Okonechnikov, Konstantin |
collection | PubMed |
description | BACKGROUND: Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas. METHODS: We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques. RESULTS: We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study. CONCLUSION: Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar “lineage of origin.” |
format | Online Article Text |
id | pubmed-10547518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105475182023-10-04 Mapping pediatric brain tumors to their origins in the developing cerebellum Okonechnikov, Konstantin Joshi, Piyush Sepp, Mari Leiss, Kevin Sarropoulos, Ioannis Murat, Florent Sill, Martin Beck, Pengbo Chan, Kenneth Chun-Ho Korshunov, Andrey Sah, Felix Deng, Maximilian Y Sturm, Dominik DeSisto, John Donson, Andrew M Foreman, Nicholas K Green, Adam L Robinson, Giles Orr, Brent A Gao, Qingsong Darrow, Emily Hadley, Jennifer L Northcott, Paul A Gojo, Johannes Kawauchi, Daisuke Hovestadt, Volker Filbin, Mariella G von Deimling, Andreas Zuckermann, Marc Pajtler, Kristian W Kool, Marcel Jones, David T W Jäger, Natalie Kutscher, Lena M Kaessmann, Henrik Pfister, Stefan M Neuro Oncol Pediatric Neuro-Oncology BACKGROUND: Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas. METHODS: We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques. RESULTS: We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study. CONCLUSION: Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar “lineage of origin.” Oxford University Press 2023-08-03 /pmc/articles/PMC10547518/ /pubmed/37534924 http://dx.doi.org/10.1093/neuonc/noad124 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 | Pediatric Neuro-Oncology Okonechnikov, Konstantin Joshi, Piyush Sepp, Mari Leiss, Kevin Sarropoulos, Ioannis Murat, Florent Sill, Martin Beck, Pengbo Chan, Kenneth Chun-Ho Korshunov, Andrey Sah, Felix Deng, Maximilian Y Sturm, Dominik DeSisto, John Donson, Andrew M Foreman, Nicholas K Green, Adam L Robinson, Giles Orr, Brent A Gao, Qingsong Darrow, Emily Hadley, Jennifer L Northcott, Paul A Gojo, Johannes Kawauchi, Daisuke Hovestadt, Volker Filbin, Mariella G von Deimling, Andreas Zuckermann, Marc Pajtler, Kristian W Kool, Marcel Jones, David T W Jäger, Natalie Kutscher, Lena M Kaessmann, Henrik Pfister, Stefan M Mapping pediatric brain tumors to their origins in the developing cerebellum |
title | Mapping pediatric brain tumors to their origins in the developing cerebellum |
title_full | Mapping pediatric brain tumors to their origins in the developing cerebellum |
title_fullStr | Mapping pediatric brain tumors to their origins in the developing cerebellum |
title_full_unstemmed | Mapping pediatric brain tumors to their origins in the developing cerebellum |
title_short | Mapping pediatric brain tumors to their origins in the developing cerebellum |
title_sort | mapping pediatric brain tumors to their origins in the developing cerebellum |
topic | Pediatric Neuro-Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547518/ https://www.ncbi.nlm.nih.gov/pubmed/37534924 http://dx.doi.org/10.1093/neuonc/noad124 |
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