Global cellular biological processes governed by MET amplification
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE65854 | GEO | 2015/02/12
SECONDARY ACCESSION(S): PRJNA275240
REPOSITORIES: GEO
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2014-02-06 | GSE48432 | GEO
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Project description:Receptor tyrosine kinases MET and EGFR are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also help in the early part of the process. Regeneration employs effective redundancy schemes to compensate for missing signals. Elimination of any single signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling abolishes liver regeneration, prevents restoration of liver mass and leads to liver decompensation. Our results demonstrate that liver function is dependent on synchronous availability of signaling from these two pathways. The study shows that MET and EGFR separately control many non-overlapping signaling endpoints, allowing for compensation when only one of the signals is blocked. The combined elimination of the signals however was not tolerated. The results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. We used microarrays to detail the global programme of gene expression in METKO-canertinib mouse liver following a partial hepatectomy
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Project description:Increasing evidence suggests that inhibiting growth factor receptor tyrosine kinases (RTKs) signaling may modulate cellular responses to DNA-damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how the MET inhibitor tepotinib modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity-based phosphoproteomic discovery survey we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphosites that consist of the SQ motif recognized by the PIKK-related kinases ATM, ATR and PRKDC. Several substrates of the DNA damage response (DDR) were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone.
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Project description:To investigate the expression patterns driven by hyperactivated MET in MET-dependent cells, we employed LoVo colon adenocarcinoma cell line, harbouring a post-translational modification of MET that leads to its constitutive activation. We then silenced MET in LoVo cells using CRISPR/Cas9 knock-out (KO) protocol, and performed gene expression profiling analysis using data obtained from RNA-seq of cells with hyperactivated-MET versus MET-KO.
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Project description:The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
2019-09-30 | BIOMD0000000827 | BioModels
Project description:B16-F10 malignant mouse melanoma cells have been frequently used as highly metastatic cells. Based on heterogenous cell surface expression of Met/HGF (hepatocyte growth factor) receptor in B16-F10 cells, the cells were divided into Met-low and Met-high cells by flow cytometry and these populations were subjected to microarray analysis. Met-low and Met-high cells showed different expression profiles in genes involved characteristics of tumors, including stem cell maintenance, pigmentation, and angiogenesis.
2016-09-25 | GSE69741 | GEO