Single-cell sequencing maps gene expression to mutational phylogenies in PDGF- and EGF-driven gliomas

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.

Source: Molecular Systems Biology - November 24, 2016 Category: Molecular Biology Authors: Müller, S., Liu, S. J., Di Lullo, E., Malatesta, M., Pollen, A. A., Nowakowski, T. J., Kohanbash, G., Aghi, M., Kriegstein, A. R., Lim, D. A., Diaz, A. Tags: Cancer, Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology Articles Source Type: research