Comparison of EGF and PDGF driven glioblastomas.

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 these tumors. Despite years of research into tyrosine-kinase inhibitors, clinical trials have shown disappointing efficacy. One of the underlying reasons is intra-tumor heterogeneity. To assess the effect of intra-tumor heterogeneity on gene expression, we derived a general 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. A deletion in a PDGF-receptor domain involved in dimerization correlated to an up-regulation of the PI3K/AKT pathway in a proneural GBM, and ectopic expression of this mutant PDGFRA in vitro enhanced proliferation and invasiveness. Descending the phylogenetic tree of the PDGFR-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type that expresses growth and angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed a gradual up-regulation of pro-invasive genes.

• Type: Other
• Archiver: European Genome-Phenome Archive (EGA)