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C-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

ABSTRACT: c-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

PROVIDER: PRJNA413704 | ENA |

REPOSITORIES: ENA

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c-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

Project description:Aberrant c-Met activation and upregulation of its cognate ligand HGF are frequently observed in bladder cancer and have been shown to regulate downstream pathways involved in proliferation, motility, and invasion. The precise mechanism underlying HGF/c-MET mediated invasion in bladder cancer is partly addressed by this microarray dataset. HGF activates the canonical TGFb signaling pathway to enhance epithelial mesenchymal transition and bladder carcinoma invasion.

2019-08-23 | GSE104740 | GEO

c-Met activation leads to the establishment of a TGFβ receptor regulatory network required for bladder cancer invasion

Project description:Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the precise mechanisms underlying HGF/c-MET mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to the E3 ligase SMURF2 targeting the TGFβ receptor for degradation. Under these conditions SMAD7 acts as an agonist disrupting the intermolecular interactions within SMURF2, permitting SMURF2 activation. We demonstrate that HGF stimulates TGFβ signaling by inducing c-SRC mediated phosphorylation of SMURF2 at two tyrosine residues impeding SMAD7 binding and enhancing SMURF2 C2-HECT domain interaction, resulting in SMURF2 inhibition and TGFβ receptor stabilization. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. Using biologically relevant orthotopic mouse models we show that inhibition of TGFβ signaling completely prevents HGF induced bladder cancer invasion. Furthermore, we make a rationale for the use of TGFβ receptor and MEK inhibitors in the treatment of high grade non-muscle-invasive bladder cancers or early stage muscle invasive bladder cancers.

2019-08-26 | PXD014736 | Pride

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Novel functional analysis of MET exon 14 skipping alteration in driving cancer invasion and metastatic dissemination

Project description:MET exon 14 skipping alteration (MET∆14Ex) is an actionable oncogenic driver that occurs in 2-4% of non-small cell lung cancer (NSCLC) cases. However, the precise role of MET∆14Ex in tumor progression in NSCLC is poorly understood. We here demonstrate that MET∆14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, which significantly boosts tumor cell scattering and invasion as well as metastasis. To explore the key mechanisms in regulation of these phenotypes, RNA sequencing (RNA-seq) studies were conducted on HGF-treated MET∆14Ex and MET cell models in an effort to identify the global change of transcriptome signature and key functional pathways involved in MET∆14Ex-medieated tumorigenesis. Both Ingenuity pathway analysis (IPA) and gene set enrichment analysis (GSEA) revealed an induction of a tight cluster of functional pathways associated with cell movement in HGF-treated MET∆14Ex models (vs MET) in a time-dependent manner.

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c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression.

Project description:Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.

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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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