Nature Communications (Nov 2023)
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,
- Ulrich Schüller
Affiliations
- Melanie Schoof
- Research Institute Children’s Cancer Center
- Shweta Godbole
- Center for Molecular Neurobiology (ZMNH), University Medical Center, Hamburg-Eppendorf
- Thomas K. Albert
- Pediatric Hematology and Oncology, University Children’s Hospital Muenster
- Matthias Dottermusch
- Center for Molecular Neurobiology (ZMNH), University Medical Center, Hamburg-Eppendorf
- Carolin Walter
- Institute of Medical Informatics, University of Muenster
- Annika Ballast
- Pediatric Hematology and Oncology, University Children’s Hospital Muenster
- Nan Qin
- German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf
- Marlena Baca Olivera
- German Cancer Consortium (DKTK), 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
- Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf
- Stefan Rutkowski
- Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf
- Martin Sill
- Hopp Children’s Cancer Center (KiTZ)
- Julian Varghese
- Institute of Medical Informatics, University of Muenster
- Ann-Kristin Afflerbach
- Research Institute Children’s Cancer Center
- Alicia Eckhardt
- Research Institute Children’s Cancer Center
- Daniel Münter
- Pediatric Hematology and Oncology, University Children’s Hospital Muenster
- Archana Verma
- Pediatric Hematology and Oncology, 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
- German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf
- Julia E. Neumann
- Center for Molecular Neurobiology (ZMNH), University Medical Center, Hamburg-Eppendorf
- Kornelius Kerl
- Pediatric Hematology and Oncology, University Children’s Hospital Muenster
- Ulrich Schüller
- Research Institute Children’s Cancer Center
- DOI
- https://doi.org/10.1038/s41467-023-43564-w
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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::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.
