Suppression of MicroRNA-9 by Mutant EGFR Signaling Induces FOXP1 to Enhance Glioblastoma Tumorigenicity
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE53504 | GEO | 2013/12/20
SECONDARY ACCESSION(S): PRJNA232148
REPOSITORIES: GEO
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Project description:The EGF-receptor (EGFR) is amplified and mutated in glioblastoma (GBM) where its common mutation, (∆EGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ∆EGFR might exert its influence through pleiotropic effectors and we hypothesized that microRNAs (miRs) might serve such a function. To test this, we determined the miR profiles of GBM cells with activated wild type EGFR (wtEGFR) and mutant EGFR (∆EGFR) to cells with non-activated EGFR or kinase dead ∆EGFR. To identify miRs regulated by EGFR, RNA from 2 different glioma cell lines (U87 and U373) were hybridized to miR expression arrays and analyzed. Each cell type was engineered to express wild type EGFR (wtEGFR), dead kinase ∆EGFR (DK) or ∆EGFR at elevated levels similar to those observed in primary glioblastomas displaying EGFR overexpression. Parental cells expressing endogenous EGFR and wtEGFR cells stimulated with EGF for 1hr were also included in the analyses.
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Project description:Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in Glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
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Project description:Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma. We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockdown of TLR2 led to a dramatic survival advantage in glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, modulating malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment.
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Project description:Glioblastoma multiforme (GBM) is a highly aggressive and heterogeneous form of primary brain tumors, driven by a complex repertoire of oncogenic alterations, including the constitutively active epidermal growth factor receptor (EGFRvIII). EGFRvIII impacts both cell-intrinsic and non-cell autonomous aspects of GBM progression, including cell invasion, angiogenesis and modulation of the tumor microenvoiront, this is, at least in part, attributable to the release and intercellular trafficking of extracellular vesicles (EVs), heterogeneous membrane structures containing multiple bioactive macromolecules. Here we analyzed the impact of EGFRvIII on the profile of glioma EVs using a series of isogenic tumor cell lines, in which this oncogene exhibits a strong transforming activity. Thus, we observed that EGFRvIII expression alters several properties of glioma EVs, including their output and global protein composition. Using mass spectrometry, quantitative proteomic analysis and Gene Ontology terms filters, we observed that EVs released by EGFRVIII-transformed cells were enriched for extracellular exosome and focal adhesion related proteins. Among them, we validated the association of pro-invasive proteins (CD44, BSG, CD151) with EVs of EGFRvIII expressing cells, and down-regulation of exosomal markers (CD81 and CD82) in EVs of their indolent counterparts. Nano-flow cytometry revealed that the EV output from individual glioma cell lines was highly heterogeneous, such that only a fraction of EVs contained specific proteins such as EGFR, CD9, or others. Notably, cells expressing EGFRvIII released ample EVs double positive for CD44/BSG, and these proteins also co-localized in cellular filopodia. We also detected the expression of homophilic adhesion molecules and increased homologous EV uptake by EGFRvIII-positive glioma cells. These results suggest that oncogenic EGFRvIII reprograms the proteome of GBM-related EVs, a notion with considerable implications for their biological activity and properties relevant for development of EV-based cancer biomarkers.
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Project description:EGFRvIII is the most common deletion mutant of EGFR in human cancer and its levels are highly correlated with poor prognosis in GBM. The deletion of exons 2-7 removes most of the extracellular ligand binding domain, so it is unable to bind EGF or other EGFR-binding ligands. Nevertheless, the mutant receptor is constitutively phosphorylated, and is capable of activating downstream signaling pathways at a low level. To comprehensively identify the downstream signaling consequences of the EGFRvIII, we incorporated phosphoproteomic, transcription profiling and DNase-Seq data from U87MG glioblastoma cells expressing titrated levels of this mutant receptor.
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