TY - JOUR
T1 - Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypes
AU - Stieber, Daniel
AU - Golebiewska, Anna
AU - Evers, Lisa
AU - Lenkiewicz, Elizabeth
AU - Brons, Nicolaas H.C.
AU - Nicot, Nathalie
AU - Oudin, Anaïs
AU - Bougnaud, Sébastien
AU - Hertel, Frank
AU - Bjerkvig, Rolf
AU - Vallar, Laurent
AU - Barrett, Michael T.
AU - Niclou, Simone P.
N1 - Funding Information:
Acknowledgments We are grateful to Virginie Baus and Wim Ammerlaan for technical assistance, and we thank the Clinical and epidemiological Investigation Center (CIeC) of CrP-Santé for help in tumour collection. We thank Christel Herold-Mende (Department of Neurosurgery, University of Heidelberg, germany) and Håkan Hedman (Department of radiation Sciences, Oncology, Umeå University, Sweden) for providing glioma stem-like cell lines. This work was supported by the Centre de recherche Public de la Santé (CrP-Santé), the Fonds National de la recherche (FNr) of luxembourg (gBM_Targets C08/BM/12 and eSCAPe 784322 BM) and the Integrated BioBank of luxembourg (IBBl).
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Array CGH
KW - Cancer stem cell
KW - Clonal evolution
KW - Flow cytometry
KW - Glioma
KW - Ploidy
KW - Single cell array CGH
UR - http://www.scopus.com/inward/record.url?scp=84896697126&partnerID=8YFLogxK
U2 - 10.1007/s00401-013-1196-4
DO - 10.1007/s00401-013-1196-4
M3 - Article
C2 - 24154962
AN - SCOPUS:84896697126
SN - 0001-6322
VL - 127
SP - 203
EP - 219
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -