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

Melanie Schoof, Shweta Godbole, Thomas K. Albert, Matthias Dottermusch, Carolin Walter, Annika Ballast, Nan Qin, Marlena Baca Olivera, Carolin Göbel, Sina Neyazi, Dörthe Holdhof, Catena Kresbach, Levke-Sophie Peter, Gefion Dorothea Epplen, Vanessa Thaden, Michael Spohn, Mirjam Blattner-Johnson, Franziska Modemann, Martin Mynarek, Stefan Rutkowski, Martin Sill, Julian Varghese, Ann-Kristin Afflerbach, Alicia Eckhardt, Daniel Münter, Archana Verma, Nina Struve, David T. W. Jones, Marc Remke, Julia E. Neumann, Kornelius Kerl and Ulrich Schüller ()
Additional contact information
Melanie Schoof: Research Institute Children’s Cancer Center
Shweta Godbole: University Medical Center, Hamburg-Eppendorf
Thomas K. Albert: University Children’s Hospital Muenster
Matthias Dottermusch: University Medical Center, Hamburg-Eppendorf
Carolin Walter: University of Muenster
Annika Ballast: University Children’s Hospital Muenster
Nan Qin: Partner Site Essen/Düsseldorf
Marlena Baca Olivera: Partner Site Essen/Düsseldorf
Carolin Göbel: Research Institute Children’s Cancer Center
Sina Neyazi: Research Institute Children’s Cancer Center
Dörthe Holdhof: Research Institute Children’s Cancer Center
Catena Kresbach: Research Institute Children’s Cancer Center
Levke-Sophie Peter: Research Institute Children’s Cancer Center
Gefion Dorothea Epplen: Research Institute Children’s Cancer Center
Vanessa Thaden: Research Institute Children’s Cancer Center
Michael Spohn: Research Institute Children’s Cancer Center
Mirjam Blattner-Johnson: Hopp Children’s Cancer Center (KiTZ)
Franziska Modemann: Mildred Scheel Cancer Career Center HaTriCS4 University Medical Center Hamburg-Eppendorf
Martin Mynarek: University Medical Center, Hamburg-Eppendorf
Stefan Rutkowski: University Medical Center, Hamburg-Eppendorf
Martin Sill: Hopp Children’s Cancer Center (KiTZ)
Julian Varghese: University of Muenster
Ann-Kristin Afflerbach: Research Institute Children’s Cancer Center
Alicia Eckhardt: Research Institute Children’s Cancer Center
Daniel Münter: University Children’s Hospital Muenster
Archana Verma: University Children’s Hospital Muenster
Nina Struve: Mildred Scheel Cancer Career Center HaTriCS4 University Medical Center Hamburg-Eppendorf
David T. W. Jones: Hopp Children’s Cancer Center (KiTZ)
Marc Remke: Partner Site Essen/Düsseldorf
Julia E. Neumann: University Medical Center, Hamburg-Eppendorf
Kornelius Kerl: University Children’s Hospital Muenster
Ulrich Schüller: Research Institute Children’s Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43564-w

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