A stromal niche regulate CSCs in Wnt-Met mammary gland tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68241 | GEO | 2018/04/23
REPOSITORIES: GEO
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Project description:The combined activation of Wnt/ß-catenin and MET/HGF is required for mammary cancer stem cell (MaCSC) maintenance. We generated mammospheres derived from tumors of mice harboring Wnt/Met signaling mutations on which we performed microarray analysis to evaluate gene expression signatures controlled by Wnt and MET pathways. We used the gene expression profiles to dissect the role and the functions of these pathways in MaCSCs. We treated mammospheres with Wnt and MET pathway inhibitors (ICG-001 and PHA665752 respectively) alone or in combination. Samples treated with DMSO were used as vehicle control.
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2014-02-18 | GSE35899 | GEO
Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel âdruggableâ candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo. PEL cells were treated with vehicle control or c-MET inhibitor PF-2341066 (0.8 µM) for 24 h, and the gene expression signature was compared to respective vehicle controls
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Project description:Co-occurrence of aberrant hepatocyte growth factor (HGF)/MET proto-oncogene receptor tyrosine kinase (MET) and Wnt/β-catenin signaling pathways has been observed in advanced and metastatic prostate cancers. This co-occurrence positively correlates with prostate cancer progression and castration-resistant prostate cancer (CRPC) development. However, the biological consequences of these abnormalities in these disease processes remain largely unknown. Here, we investigated the aberrant activation of HGF/MET and Wnt/β-catenin cascades in prostate tumorigenesis by using a newly generated mouse model in which both murine Met transgene and stabilized β-catenin are conditionally co-expressed in prostatic epithelial cells. These compound mice displayed accelerated prostate tumor formation and invasion compared with their littermates that expressed only stabilized β-catenin.RNA-Seq and qRT-PCR analyses revealed increased expression of genes associated with tumor cell proliferation, progression,and metastasis. Moreover, Wnt signaling pathways were robustly enriched in prostate tumor samples from the compound mice.ChIP-qPCR experiments revealed increased β-catenin recruitment within the regulatory regions of the Myc gene in tumor cellsof the compound mice. Interestingly, the occupancy of MET on the Myc promoter also appeared in the compound mouse tumor samples,implicating a novel role of MET in β-catenin–mediated transcription. Results from implanting prostate graft tissues derived from the compound mice and controls into HGF-transgenic mice further uncovered that HGF induces prostatic oncogenic transformation and cell growth. These results indicate a role of HGF/MET in β-catenin–mediated prostate cancer cell growth and progressionand implicate a molecular mechanism whereby nuclear MET promotes aberrant Wnt/β-catenin signaling–mediated prostate tumorigenesis.
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Project description:Cancer stem cells (CSCs) comprise a small subpopulation of undifferentiated cancer cells with the ability to self-renew and give rise to the heterogeneous cancer cell lineages that form tumorous masses. Thus, tumor eradication may be greatly improved by specifically targeting CSCs, as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft (PDX) tumors from ER-negative breast cancer patient tissue from which we isolated mammospheres, a method known to enrich for cells with CSC-properties. An unbiased, comparative global proteomic analysis using label-free mass spectrometry was performed on the patient tumor tissues and corresponding PDX tumors and mammospheres. Good concordance between the proteome profiles of patient tumor tissue and corresponding PDX tumors was observed. However, lower abundance of immune- and extracellular matrix-related proteins and higher abundance of proteins associated with cell-to-cell adhesion including desmosome proteins and β-catenin were observed in PDX versus patient tumors. Interestingly, analysis of proteins elevated in mammospheres vs. PDX tumors identified an enrichment of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis protein expression was verified in a large gene expression data set of clinical breast cancers showing correlation with shorter relapse-free survival. RNA interference and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation and growth of CSCs derived from PDX tumors and cancer cell lines. Our findings identify the cholesterol biosynthesis pathway as central for CSC growth and a potential therapeutic target for CSC as well as providing an additional mechanistic explanation for the observed benefit of statins in breast cancer treatment.
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Project description:MET, the receptor for hepatocyte growth factor (HGF), is involved in wide variety of biological events and its aberrant activation is implicated in the pathogenesis of cancer. Especially, MET signaling is associated with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), key drugs in therapy of non-small cell lung cancer. MET has 11 potential N-glycosylation sites, however, the site-specific roles of N-glycans have not been elucidated. Here, we report that N-glycans regulate proteolytic processing of MET and HGF induced MET signaling, site specifically. N-glycosylation inhibitors suppressed processing and trafficking of endogenous MET in H1975 and EBC-1 lung cancer cells and exogenous MET in CHO cells. We purified the recombinant extracellular domain of human MET and determined the site-specific N-glycan structures and occupancy using nanoflow liquid chromatography-electrospray ionization mass spectrometry. The results indicated that most sites were fully glycosylated and the dominant population were complex-type which were rich in sialic acids and core fucoses. To examine the effects of N-glycan deletion of MET, we prepared endogenous-MET-knockout Flp-In CHO cells and transfected with series of N-glycan deletion mutants of MET. It was found that several N-glycans are implicated in processing of MET. It was also suggested that the N-glycans of -subunit of MET positively regulate HGF signaling, and the N-glycans of β-subunit negatively regulate HGF signaling. In all-N-glycan deletion mutant, processing and signaling were significantly suppressed. It was observed that the cell proliferation rate was suppressed in all-N-glycan deletion mutant, although the cell surface expression levels of MET were not completely diminished. We examined the HGF biding affinity for the recombinant extracellular domain of MET and found that peptide N-glycosidase F treatment did not affect the ligand binding affinity. It was suggested that N-glycans of MET affect the status and the function of the receptor site-specifically.
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Project description:MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT (survival/migration), STAT3 (differentiation), and MAPK (proliferation). When mutated or amplified, MET becomes a "driver" for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to its "skipping" from mRNA and consequent deletion of the receptor's juxtamembrane domain (MET∆14). It is currently believed that, as in gene amplification, MET∆14 kinase is constitutively active. Analysis of MET in carcinoma cell lines showed that MET∆14 strictly depends on HGF for kinase activation. Compared to WT MET, ∆14 is sensitive to lower HGF concentrations, with more sustained kinase response, ultimately leading to a robust phosphorylation of AKT, without affecting MAPK or STAT3. This altered kinase response leads to a distinctive transcriptomic signature. Functional studies revealed that ∆14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ∆14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.
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