Genetic and functional diversity of propagating cells in glioblastoma

Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells...

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Bibliographic Details
Published in:	Stem cell reports 2015-01, Vol.4 (1), p.7-15
Main Authors:	Piccirillo, Sara G M, Colman, Sue, Potter, Nicola E, van Delft, Frederik W, Lillis, Suzanne, Carnicer, Maria-Jose, Kearney, Lyndal, Watts, Colin, Greaves, Mel
Format:	Article
Language:	eng
Subjects:	Animals Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Line, Tumor Disease Progression DNA Copy Number Variations Genetic Variation Genome-Wide Association Study Genomics Glioblastoma - genetics Glioblastoma - metabolism Glioblastoma - pathology Heterografts High-Throughput Nucleotide Sequencing Humans In Situ Hybridization, Fluorescence Mice Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Phenotype Polymorphism, Single Nucleotide Single-Cell Analysis
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Summary:	Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo.
ISSN:	2213-6711 2213-6711