Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA226603 | ENA |
REPOSITORIES: ENA
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Project description:Cancer patients often develop hemostasis disorders whose pathogenesis is poorly understood. Previous work in mouse models has shown that these disorders can be sustained by the MET oncogene by transcriptional upregulation of hemostasis genes. Here we investigated the correlation between the procoagulant state of colorectal cancer patients, and overexpression of MET and hemostasis genes in the tumor. We found that, in a patient subset, blood levels of D-dimer and coagulation factor XII (F12) were frequently elevated, and reverted towards normality after surgery. Global expression profiling of tumor tissues and adjacent mucosae revealed a significant correlation between high D-dimer levels in the blood, and overexpression of MET in the tumor. An “hemostasis gene signature”, including F12, cyclo-oxygenase 2, thromboxane synthase-1, plasminogen activator inhibitor-1, urokinase-type plasminogen activator and protein C receptor was associated with MET overexpression. This association was confirmed in an independent 173-sample CRC dataset. The mechanistic link between MET signaling and F12 expression was established experimentally in cell lines. These data indicate that MET contributes to the pathogenesis of coagulation disorders in CRC by upregulation of hemostasis genes including F12, and provide a candidate biomarker for the CRC-associated procoagulant state.
2022-12-30 | GSE52060 | GEO
Project description:Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, non-alcoholic fatty liver disease (NAFLD) is gaining importance. As the disease progresses it can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but the molecular mechanisms responsible for disease development remained unresolved. Here, we uncover a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway in primary hepatocytes from a preclinical model fed with a Western diet (WD). Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveals a patient-specific variability in basal MET phosphorylation, which correlates with the outcome of patients after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
2024-01-16 | MODEL2306280002 | BioModels
Project description:Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction remain largely unexplored. We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models and ex vivo non-small cell lung cancer patient organotypic cultures. We identified an ‘oncogene addiction phosphorylation signature’ (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments.
2023-03-11 | PXD037406 | Pride
Project description:Mathematical model of the mechanism and kinetics of blood coagulation factor XII.
2018-08-16 | MODEL1808160001 | BioModels
Project description:Mathematical model of blood coagulation with platelet activation. Model includes factor XII, factor VIIIa fragments, meizothrombin, kallikrein, C1-inhibitor, alpha1-Antitrypsin, alpha2-Antiplasmin, fibrinogen and fibrillin.
2018-07-18 | MODEL1807180003 | BioModels
Project description:Human-specific changes in specific Siglecs is one of the reasons put forth as molecular mechanisms that could explain human proneness to developing cancers. The SIGLEC12 gene, which encodes the Siglec-XII protein mainly found on epithelial cells, has a fixed homozygous missense mutation in a critical arginine renders unable to recognize its natural ligand. Additionally, the gene harbors a polymorphic frameshift mutation that eliminates expression of the full-length protein in most humans. We hypothesized that dysfunctional Siglec-XII is involved in cancer progression in humans' epithelia. Here we report that the transgenic conditional expression of human Siglec-XII in mouse intestinal epithelia increased the number and size of cancers in a model of colitis-associated colorectal carcinoma (AOM/DSS). RNA sequencing of the colons at baseline and after AOM/DSS challenge derived a gene signature comprised of the differentially expressed genes (DEGs) between controls (Villin1-Cre-ER(T2)) and Siglec-XII-expressing mice, showing that upregulated DEGs in Siglec-XII mice were enriched for diverse bioenergetic processes.
2024-03-27 | GSE262087 | GEO
Project description:This experiment investigates In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. The goal of this study was to examine the effects of AMG337 on proliferation in cancer cell lines with varying MET copy number, the hypothesis being that high-level focal MET amplification is required to confer MET oncogene addiction and AMG337 sensitivity.
2016-05-04 | GSE77414 | GEO
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.
2019-12-17 | GSE142158 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE27854: Overexpression of NUCKS1 in colorectal cancer correlates with recurrence after curative surgery (gene expression analysis) GSE27910: Overexpression of NUCKS1 in colorectal cancer correlates with recurrence after curative surgery (copy number analysis) Refer to individual Series
2012-10-16 | E-GEOD-27913 | biostudies-arrayexpress
Project description:The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in HPV-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4-protein interactions in cervical cancer cells and reveal that Methyl-binding proteins (MBD2 and MBD3), are determinants of Oct4 driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re-expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate transcription by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.
2023-12-11 | GSE248367 | GEO