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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.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001002269 Illumina HiSeq 4000 1
EGAD00001002270 Illumina HiSeq 2500 1
EGAD00001002271 Illumina HiSeq 2500 1
EGAD00001002272 Illumina HiSeq 2500 1
EGAD00001002273 Illumina HiSeq 2500 1
EGAD00001002274 Illumina HiSeq 2500 1
EGAD00001002275 Illumina HiSeq 2500 1
Publications Citations
Single-cell sequencing maps gene expression to mutational phylogenies in PDGF- and EGF-driven gliomas.
Mol Syst Biol 12: 2016 889
62
Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment.
Genome Biol 18: 2017 234
331
Isoform-level gene expression patterns in single-cell RNA-sequencing data.
Bioinformatics 34: 2018 2392-2400
9
Cell-level somatic mutation detection from single-cell RNA sequencing.
Bioinformatics 35: 2019 4679-4687
26
The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation.
Cancer Discov 9: 2019 1708-1719
150
Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states.
Nat Genet 53: 2021 1469-1479
75
Phagocytosis of Glioma Cells Enhances the Immunosuppressive Phenotype of Bone Marrow-Derived Macrophages.
Cancer Res 83: 2023 771-785
6
Glioblastoma heterogeneity at single cell resolution.
Oncogene 42: 2023 2155-2165
14
Dissecting the tumor microenvironment of epigenetically driven gliomas: Opportunities for single-cell and spatial multiomics.
Neurooncol Adv 5: 2023 vdad101
0