TY  - JOUR
AU  - Schoof, Melanie
AU  - Godbole, Shweta
AU  - Albert, Thomas K
AU  - Dottermusch, Matthias
AU  - Walter, Carolin
AU  - Ballast, Annika
AU  - Qin, Nan
AU  - Olivera, Marlena Baca
AU  - Göbel, Carolin
AU  - Neyazi, Sina
AU  - Holdhof, Dörthe
AU  - Kresbach, Catena
AU  - Peter, Levke-Sophie
AU  - Epplen, Gefion Dorothea
AU  - Thaden, Vanessa
AU  - Spohn, Michael
AU  - Blattner-Johnson, Mirjam
AU  - Modemann, Franziska
AU  - Mynarek, Martin
AU  - Rutkowski, Stefan
AU  - Sill, Martin
AU  - Varghese, Julian
AU  - Afflerbach, Ann-Kristin
AU  - Eckhardt, Alicia
AU  - Münter, Daniel
AU  - Verma, Archana
AU  - Struve, Nina
AU  - Jones, David
AU  - Remke, Marc
AU  - Neumann, Julia E
AU  - Kerl, Kornelius
AU  - Schüller, Ulrich
TI  - Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-02477
SP  - 7717
PY  - 2023
AB  - 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::Trp53Fl/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.
KW  - Humans
KW  - Child
KW  - Mice
KW  - Animals
KW  - N-Myc Proto-Oncogene Protein: genetics
KW  - N-Myc Proto-Oncogene Protein: metabolism
KW  - Neuroblastoma: metabolism
KW  - Disease Models, Animal
KW  - Glioma: genetics
KW  - Mutation
KW  - Gene Amplification
KW  - N-Myc Proto-Oncogene Protein (NLM Chemicals)
KW  - MYCN protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38001143
C2  - pmc:PMC10673884
DO  - DOI:10.1038/s41467-023-43564-w
UR  - https://inrepo02.dkfz.de/record/285654
ER  -