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

Author

Listed:
  • Melanie Schoof

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Shweta Godbole

    (University Medical Center, Hamburg-Eppendorf)

  • Thomas K. Albert

    (University Children’s Hospital Muenster)

  • Matthias Dottermusch

    (University Medical Center, Hamburg-Eppendorf
    University Medical Center, Hamburg-Eppendorf)

  • Carolin Walter

    (University of Muenster)

  • Annika Ballast

    (University Children’s Hospital Muenster)

  • Nan Qin

    (Partner Site Essen/Düsseldorf
    Heinrich Heine University, University Hospital Düsseldorf
    Heinrich Heine University, University Hospital Düsseldorf
    Heinrich-Heine-University Düsseldorf)

  • Marlena Baca Olivera

    (Partner Site Essen/Düsseldorf
    Heinrich Heine University, University Hospital Düsseldorf
    Heinrich Heine University, University Hospital Düsseldorf
    Heinrich-Heine-University Düsseldorf)

  • Carolin Göbel

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Sina Neyazi

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Dörthe Holdhof

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Catena Kresbach

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf
    University Medical Center, Hamburg-Eppendorf
    Mildred Scheel Cancer Career Center HaTriCS4 University Medical Center Hamburg-Eppendorf)

  • Levke-Sophie Peter

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Gefion Dorothea Epplen

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Vanessa Thaden

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Michael Spohn

    (Research Institute Children’s Cancer Center)

  • Mirjam Blattner-Johnson

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Franziska Modemann

    (Mildred Scheel Cancer Career Center HaTriCS4 University Medical Center Hamburg-Eppendorf
    University Medical Center Hamburg-Eppendorf)

  • Martin Mynarek

    (University Medical Center, Hamburg-Eppendorf
    Mildred Scheel Cancer Career Center HaTriCS4 University Medical Center Hamburg-Eppendorf)

  • Stefan Rutkowski

    (University Medical Center, Hamburg-Eppendorf)

  • Martin Sill

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Julian Varghese

    (University of Muenster)

  • Ann-Kristin Afflerbach

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Alicia Eckhardt

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf
    Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf)

  • 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
    Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf)

  • David T. W. Jones

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Marc Remke

    (Partner Site Essen/Düsseldorf
    Heinrich Heine University, University Hospital Düsseldorf
    Heinrich Heine University, University Hospital Düsseldorf
    Heinrich-Heine-University Düsseldorf)

  • Julia E. Neumann

    (University Medical Center, Hamburg-Eppendorf
    University Medical Center, Hamburg-Eppendorf)

  • Kornelius Kerl

    (University Children’s Hospital Muenster)

  • Ulrich Schüller

    (Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf
    University Medical Center, Hamburg-Eppendorf)

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.

Suggested Citation

  • 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 Kre, 2023. "Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43564-w
    DOI: 10.1038/s41467-023-43564-w
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