title: Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts.
abstract: Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3)(Fl/+)Trp53 (Fl/Fl) mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Feodor-Lynen-Strasse 23, 81377, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Pöschl
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stark
authors.forename: Philipp
authors.initials: P
authors.lastname: Neumann
authors.forename: Susanne
authors.initials: S
authors.lastname: Gröbner
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawauchi
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
mesh_terms: D000328:Adult; D000367:Age Factors; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human