Chromosome topology of the EGFR locus in glioblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA579586 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10349200.fastq.gz | Fastqsanger.gz | |||
| SRR10349191.fastq.gz | Fastqsanger.gz | |||
| SRR10349192.fastq.gz | Fastqsanger.gz | |||
| SRR10349193.fastq.gz | Fastqsanger.gz | |||
| SRR10349194.fastq.gz | Fastqsanger.gz |
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Project description:Here we have used 4C-seq to interrogate the toplogy of the EGFR locus in glioblastoma models that are EGFR unamplified (GSC23) and amplified (GBM3565).
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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, the most frequent and malignant adult brain tumor has been extensively studied; yet no effective treatment exists. To overcome this dismal scenario, it is essential to improve preclinical biological models. This study aimed to establish and molecularly characterize glioblastoma primary cultures. Additionally, it intended to assess the efficacy of molecular-targeted therapies, in the presence of putative targeting cell lines. Five glioblastoma primary cultures were established exhibiting a diversity of chromosomal alterations by aCGH, with gain of chromosome 7 and loss of chromosome 10, 13 and 17p, the most frequent alterations. Mutation profiling by Ion Torrent and Sanger sequencing showed the present of hotspot mutations in TERT (4/5), TP53 (2/5) and RB, BRAF, PTEN and EGFR (1/5). A similar chromosomal and mutation pattern was observed in the primary cultures and matched frozen tumors. The MTS cell viability assay of the p.Gly598Val EGFR mutated cell line, revealed AST1306 as the most potent EGFR inhibitor, when compared with afatinib, erlotinib, or lapatinib. Herein, glioblastoma primary cultures were successfully established and molecularly characterized. Importantly, we showed that AST1306 inhibits EGFR mutated cells, suggesting that primary cultures are suitable in vitro models for glioblastoma biology and preclinical drugs studies. Two-color Agilent 8x60K array CGH (aCGH) was performed in 10 glioblastoma multiforme samples (CY3) and reference DNA (CY5). The 10 glioblastoma multiforme samples were: DNA extracted from 5 primary cultured cells; DNA of 5 primary tumors (matched with the 5 primary cell lines). Gender-matched commercial DNA of each case was used as control.
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