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- Title
Single-cell sequencing maps gene expression to mutational phylogenies in PDGF- and EGF-driven gliomas.
- Authors
Müller, Sören; Liu, Siyuan John; Di Lullo, Elizabeth; Malatesta, Martina; Pollen, Alex A; Nowakowski, Tomasz J; Kohanbash, Gary; Aghi, Manish; Kriegstein, Arnold R; Lim, Daniel A; Diaz, Aaron
- Abstract
Glioblastoma multiforme ( GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth factor ( EGF) and platelet-derived growth factor ( PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in GBM. However, clinical trials of tyrosine-kinase inhibitors have shown disappointing efficacy, in part due to intra-tumor heterogeneity. To assess the effect of clonal heterogeneity on gene expression, we derived an approach to map single-cell expression profiles to sequentially acquired mutations identified from exome sequencing. Using 288 single cells, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. Descending the phylogenetic tree of a PDGF-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type, expressing pro-angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed an up-regulation of pro-invasive genes. An in-frame deletion in a specific dimerization domain of PDGF receptor correlates with an up-regulation of growth pathways in a proneural GBM and enhances proliferation when ectopically expressed in glioma cell lines. In-frame deletions in this domain are frequent in public GBM data.
- Subjects
GLIOBLASTOMA multiforme; BRAIN tumors; PLATELET-derived growth factor; MOLECULAR phylogeny; GLIOMAS; EXOMES
- Publication
Molecular Systems Biology, 2016, Vol 12, Issue 11, pn/a
- ISSN
1744-4292
- Publication type
Article
- DOI
10.15252/msb.20166969