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Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation

Sandén, Emma LU ; Dyberg, Cecilia; Krona, Cecilia; Gallo-Oller, Gabriel; Olsen, Thale Kristin; Enríquez Pérez, Julio LU ; Wickström, Malin; Estekizadeh, Atosa; Kool, Marcel and Visse, Edward LU , et al. (2017) In Scientific Reports 7.
Abstract

Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice. Mice developed symptoms of brain tumours with a latency of 17-18 weeks. Neurosphere cultures were re-established and serially transplanted for 3 generations, with a negative... (More)

Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice. Mice developed symptoms of brain tumours with a latency of 17-18 weeks. Neurosphere cultures were re-established and serially transplanted for 3 generations, with a negative correlation between tumour latency and numbers of injected cells. Xenografts replicated the phenotype of the primary tumour, including high degree of clustering in DNA methylation analysis, high proliferation, expression of tumour markers, MYC amplification and elevated MYC expression, and sensitivity to the MYC inhibitor JQ1. Xenografts maintained maintained expression of tumour-derived VEGFA and stromal-derived COX-2. VEGFA, COX-2 and c-Myc are highly expressed in Group 3 compared to other medulloblastoma subgroups, suggesting that these molecules are relevant therapeutic targets in Group 3 medulloblastoma.

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Scientific Reports
volume
7
publisher
Nature Publishing Group
external identifiers
  • scopus:85017614633
  • wos:000399363300001
ISSN
2045-2322
DOI
10.1038/srep46366
language
English
LU publication?
yes
id
62dfa5c9-b06b-42d2-bd16-1eab0bcd803f
date added to LUP
2017-05-08 11:32:49
date last changed
2017-09-18 11:35:17
@article{62dfa5c9-b06b-42d2-bd16-1eab0bcd803f,
  abstract     = {<p>Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice. Mice developed symptoms of brain tumours with a latency of 17-18 weeks. Neurosphere cultures were re-established and serially transplanted for 3 generations, with a negative correlation between tumour latency and numbers of injected cells. Xenografts replicated the phenotype of the primary tumour, including high degree of clustering in DNA methylation analysis, high proliferation, expression of tumour markers, MYC amplification and elevated MYC expression, and sensitivity to the MYC inhibitor JQ1. Xenografts maintained maintained expression of tumour-derived VEGFA and stromal-derived COX-2. VEGFA, COX-2 and c-Myc are highly expressed in Group 3 compared to other medulloblastoma subgroups, suggesting that these molecules are relevant therapeutic targets in Group 3 medulloblastoma.</p>},
  articleno    = {46366},
  author       = {Sandén, Emma and Dyberg, Cecilia and Krona, Cecilia and Gallo-Oller, Gabriel and Olsen, Thale Kristin and Enríquez Pérez, Julio and Wickström, Malin and Estekizadeh, Atosa and Kool, Marcel and Visse, Edward and Ekström, Tomas J. and Siesjö, Peter and Inge Johnsen, John and Darabi, Anna},
  issn         = {2045-2322},
  language     = {eng},
  month        = {04},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation},
  url          = {http://dx.doi.org/10.1038/srep46366},
  volume       = {7},
  year         = {2017},
}