Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypes

Daniel Stieber, Anna Golebiewska, Lisa Evers, Elizabeth Lenkiewicz, Nicolaas H.C. Brons, Nathalie Nicot, Anaïs Oudin, Sébastien Bougnaud, Frank Hertel, Rolf Bjerkvig, Laurent Vallar, Michael T. Barrett, Simone P. Niclou

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Glioblastoma (GBM) is known to be a heterogeneous disease; however, the genetic composition of the cells within a given tumour is only poorly explored. In the advent of personalised medicine the understanding of intra-tumoural heterogeneity at the cellular and the genetic level is mandatory to improve treatment and clinical outcome. By combining ploidy-based flow sorting with array-comparative genomic hybridization we show that primary GBMs present as either mono- or polygenomic tumours (64 versus 36 %, respectively). Monogenomic tumours were limited to a pseudodiploid tumour clone admixed with normal stromal cells, whereas polygenomic tumours contained multiple tumour clones, yet always including a pseudodiploid population. Interestingly, pseudodiploid and aneuploid fractions carried the same aberrations as defined by identical chromosomal breakpoints, suggesting that evolution towards aneuploidy is a late event in GBM development. Interestingly, while clonal heterogeneity could be recapitulated in spheroid-based xenografts, we find that genetically distinct clones displayed different tumourigenic potential. Moreover, we show that putative cancer stem cell markers including CD133, CD15, A2B5 and CD44 were present on genetically distinct tumour cell populations. These data reveal the clonal heterogeneity of GBMs at the level of DNA content, tumourigenic potential and stem cell marker expression, which is likely to impact glioma progression and treatment response. The combined knowledge of intra-tumour heterogeneity at the genetic, cellular and functional level is crucial to assess treatment responses and to design personalized treatment strategies for primary GBM.

Original languageEnglish (US)
Pages (from-to)203-219
Number of pages17
JournalActa neuropathologica
Volume127
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Array CGH
  • Cancer stem cell
  • Clonal evolution
  • Flow cytometry
  • Glioma
  • Ploidy
  • Single cell array CGH

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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