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Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures

Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical charact...

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Autores principales: Schoof, Melanie, Godbole, Shweta, Albert, Thomas K., Dottermusch, Matthias, Walter, Carolin, Ballast, Annika, Qin, Nan, Olivera, Marlena Baca, Göbel, Carolin, Neyazi, Sina, Holdhof, Dörthe, Kresbach, Catena, Peter, Levke-Sophie, Epplen, Gefion Dorothea, Thaden, Vanessa, Spohn, Michael, Blattner-Johnson, Mirjam, Modemann, Franziska, Mynarek, Martin, Rutkowski, Stefan, Sill, Martin, Varghese, Julian, Afflerbach, Ann-Kristin, Eckhardt, Alicia, Münter, Daniel, Verma, Archana, Struve, Nina, Jones, David T. W., Remke, Marc, Neumann, Julia E., Kerl, Kornelius, Schüller, Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673884/
https://www.ncbi.nlm.nih.gov/pubmed/38001143
http://dx.doi.org/10.1038/s41467-023-43564-w
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author Schoof, Melanie
Godbole, Shweta
Albert, Thomas K.
Dottermusch, Matthias
Walter, Carolin
Ballast, Annika
Qin, Nan
Olivera, Marlena Baca
Göbel, Carolin
Neyazi, Sina
Holdhof, Dörthe
Kresbach, Catena
Peter, Levke-Sophie
Epplen, Gefion Dorothea
Thaden, Vanessa
Spohn, Michael
Blattner-Johnson, Mirjam
Modemann, Franziska
Mynarek, Martin
Rutkowski, Stefan
Sill, Martin
Varghese, Julian
Afflerbach, Ann-Kristin
Eckhardt, Alicia
Münter, Daniel
Verma, Archana
Struve, Nina
Jones, David T. W.
Remke, Marc
Neumann, Julia E.
Kerl, Kornelius
Schüller, Ulrich
author_facet Schoof, Melanie
Godbole, Shweta
Albert, Thomas K.
Dottermusch, Matthias
Walter, Carolin
Ballast, Annika
Qin, Nan
Olivera, Marlena Baca
Göbel, Carolin
Neyazi, Sina
Holdhof, Dörthe
Kresbach, Catena
Peter, Levke-Sophie
Epplen, Gefion Dorothea
Thaden, Vanessa
Spohn, Michael
Blattner-Johnson, Mirjam
Modemann, Franziska
Mynarek, Martin
Rutkowski, Stefan
Sill, Martin
Varghese, Julian
Afflerbach, Ann-Kristin
Eckhardt, Alicia
Münter, Daniel
Verma, Archana
Struve, Nina
Jones, David T. W.
Remke, Marc
Neumann, Julia E.
Kerl, Kornelius
Schüller, Ulrich
author_sort Schoof, Melanie
collection PubMed
description Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53(Fl/Fl)::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.
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spelling pubmed-106738842023-11-24 Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures Schoof, Melanie Godbole, Shweta Albert, Thomas K. Dottermusch, Matthias Walter, Carolin Ballast, Annika Qin, Nan Olivera, Marlena Baca Göbel, Carolin Neyazi, Sina Holdhof, Dörthe Kresbach, Catena Peter, Levke-Sophie Epplen, Gefion Dorothea Thaden, Vanessa Spohn, Michael Blattner-Johnson, Mirjam Modemann, Franziska Mynarek, Martin Rutkowski, Stefan Sill, Martin Varghese, Julian Afflerbach, Ann-Kristin Eckhardt, Alicia Münter, Daniel Verma, Archana Struve, Nina Jones, David T. W. Remke, Marc Neumann, Julia E. Kerl, Kornelius Schüller, Ulrich Nat Commun Article Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53(Fl/Fl)::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from. Nature Publishing Group UK 2023-11-24 /pmc/articles/PMC10673884/ /pubmed/38001143 http://dx.doi.org/10.1038/s41467-023-43564-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Schoof, Melanie
Godbole, Shweta
Albert, Thomas K.
Dottermusch, Matthias
Walter, Carolin
Ballast, Annika
Qin, Nan
Olivera, Marlena Baca
Göbel, Carolin
Neyazi, Sina
Holdhof, Dörthe
Kresbach, Catena
Peter, Levke-Sophie
Epplen, Gefion Dorothea
Thaden, Vanessa
Spohn, Michael
Blattner-Johnson, Mirjam
Modemann, Franziska
Mynarek, Martin
Rutkowski, Stefan
Sill, Martin
Varghese, Julian
Afflerbach, Ann-Kristin
Eckhardt, Alicia
Münter, Daniel
Verma, Archana
Struve, Nina
Jones, David T. W.
Remke, Marc
Neumann, Julia E.
Kerl, Kornelius
Schüller, Ulrich
Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
title Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
title_full Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
title_fullStr Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
title_full_unstemmed Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
title_short Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
title_sort mouse models of pediatric high-grade gliomas with mycn amplification reveal intratumoral heterogeneity and lineage signatures
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673884/
https://www.ncbi.nlm.nih.gov/pubmed/38001143
http://dx.doi.org/10.1038/s41467-023-43564-w
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