Co-dependency for MET and FGFR1 in basal triple negative breast cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA681227 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13159368_1.fastq.gz | Fastqsanger.gz | |||
| SRR13159368_2.fastq.gz | Fastqsanger.gz | |||
| SRR13159369_1.fastq.gz | Fastqsanger.gz | |||
| SRR13159369_2.fastq.gz | Fastqsanger.gz | |||
| SRR13159370_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks both effective patient stratification strategies and therapeutic targets. In the present study, we assay tumour-initiating cells (TICs) properties, using established Met-dependent transgenic mouse models of TNBC, breast cancer cell lines and, patient-derived xenografts, to directly investigate the role of Met in tumour initiation and identify FGFR1 signaling as a key convergent pathway with Met for the maintenance of TICs. To understand the events that occur in TICs upon inhibition of Met and FGFR1, we performed gene expression profiling by RNA-Sequencing of RNA prepared from tumoursphere from 3 independent MMTV-Metmt;Trp53fl/+;Cre derived spindloid tumour cell lines (A1005, A1129, A1471) following treatment with Met or FGFR inhibitor alone (Crizotinib or PD173074, respectively), or in combination for 24h.
2020-11-28 | GSE162272 | GEO
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks both effective patient stratification strategies and therapeutic targets. Whilst elevated levels of the MET receptor tyrosine kinase are associated with TNBCs and predict poor clinical outcome, the functional role of MET in TNBC is still poorly understood. In this study, we utilise an established Met-dependent transgenic mouse model of TNBC, human cell lines and patient-derived xenografts to investigate the role of MET in TNBC tumorigenesis. We find that in TNBCs with mesenchymal signatures, MET participates in a compensatory interplay with FGFR1 to regulate tumour-initiating cells (TICs). We demonstrate a requirement for the scaffold protein FRS2 downstream from both Met and FGFR1 and find that dual inhibition of MET and FGFR1 signalling results in TIC depletion, hindering tumour progression. Importantly, basal breast cancers that display elevated MET and FGFR1 signatures are associated with poor relapse-free survival. Our results support a role for MET and FGFR1 as potential co-targets for anti-TIC therapies in TNBC.
| S-EPMC7997957 | biostudies-literature
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2 32 array samples
2012-05-29 | E-GEOD-28712 | biostudies-arrayexpress
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2
2012-05-30 | GSE28712 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.
2024-01-15 | PXD043007 | Pride
Project description:Elevated Met receptor tyrosine kinase (RTK) expression correlates with poor outcome in breast cancer, yet a causal role for Met in the development of breast cancer has not been directly established. To examine this question, we generated a transgenic mouse model that targets expression of an oncogenic Met receptor (MetMut) to the mammary epithelium. We show that MetMut induces mammary tumors with a variety of histopathologies that exhibit gene expression profiles sharing similarities with human basal and luminal breast tumor subtypes. Among all breast cancers, we further demonstrate that the Met receptor is primarily overexpressed in human basal and HER2 positive breast cancers, and that a Met associated gene expression signature identifies patients with poor prognosis. Keywords: Met, mammary, poor outcome, EMT, basal breast cancer
2009-03-30 | GSE10450 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.
2024-01-15 | PXD041563 | Pride
Project description:Mammary specific deletion of Lfng induces basal-like and claudin-low tumors with accumulation of Notch intracellular domain fragments, increased expression of proliferation-associated Notch targets, amplification of the Met/Caveolin locus, and elevated Met and Igf-1R signaling.
2012-05-30 | GSE35855 | GEO
Project description:We used microarrays to probe the global programme of gene expression under treatment with c-Met inhibitor and identified distinct classes of up- and down-regulated genes during this process We treated MET addicted EBC-1 and MKN-45 cells with selective c-Met kinase inhibitor SGX-523 at 1uM for 24 and 48 hours, using HCC827 cells with activated c-Met but lacking MET dependency as a negative control
2015-02-12 | E-GEOD-65854 | biostudies-arrayexpress
Project description:Triple-negative (TN) and Basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormonal receptors (HR) and overexpression and/or amplification of HER2. However, both classifications when compared to each other, show substantial discordance rates. Here, we molecularly characterize TN tumors, and Basal-like tumors, and compare and contrast the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 Basal-like tumors, 21.4% and 31.5% were identified as non-Basal-like and non-TN, respectively. TN tumors identified as Luminal or HER2-enriched showed undistinguishable overall gene expression profiles when compared versus Luminal or HER2-enriched tumors that were not TN. Similar findings were observed within Basal-like tumors regardless of the TN status. Interestingly, most TN tumors identified as HER2-enriched showed low HER2 expression and lack of HER2 amplification despite the similar overall gene expression profiles to HER2-E tumors that were not TN. Lastly, additional genomic classifications are examined within TN and Basal-like cancers, most of which are largely concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based on Basal-like versus non-Basal-like gene expression profiles as this appears to be the main biological difference seen within TN breast cancer patients. reference x sample
2014-07-29 | E-GEOD-41119 | biostudies-arrayexpress