Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma

Xiumei Zhao, Zhigang Liu, Litian Yu, Yujing Zhang, Patricia Baxter, Horatiu Voicu, Sivashankarappa Gurusiddappa, Joseph Luan, Jack M. Su, Hon Chiu Eastwood Leung, Xiao Nan Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

We previously showed that primary tumor-based orthotopic xenograft mouse models of medulloblastoma replicated the histopathological phenotypes of patients original tumors. Here, we performed global gene expression profiling of 11 patient-specific xenograft models to further determine whether the xenograft tumors were molecularly accurate during serial subtransplantations in mouse brains and whether they represented all the molecular subtypes of medulloblastoma that were recently described. Analysis of the transcriptomes of 9 pairs of matched passage I xenografts and patients tumors revealed high correlation coefficients (r 2 > 0.95 in 5 models, > 0.9 in 3 models, and > 0.85 in 1 model) and only identified 69 genes in which expressions were altered (FDR =0.0023). Subsequent pair-wise comparisons between passage I, III, and V xenografts from the 11 models further showed that no dramatic alterations were introduced (r 2 > 0.9 in 8 models and > 0.8 in 3 models). The genetic abnormalities of each model were then identified through comparison with control RNAs from 5 normal cerebella and 2 fetal brains. Hierarchical clustering using 3 previously published molecular signatures showed that our models span the whole spectrum of molecular subtypes, including SHH (n = 2), WNT (n = 2), and the most recently identified group C (n = 4) and group D (n = 3). In conclusion, we demonstrated that the 11 orthotopic medulloblastoma xenograft models were molecularly faithful to the primary tumors, and our comprehensive collection of molecularly distinct animal models should serve as a valuable resource for the development of new targeted therapies for medulloblastoma.

Original languageEnglish (US)
Pages (from-to)574-583
Number of pages10
JournalNeuro-oncology
Volume14
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • Cancer stem cell
  • Glioma
  • Medulloblastoma
  • Orthotopic xenograft model

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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