References of "Noël, Agnès"
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See detailFunctional analysis of dual-specificity protein phosphatases in angiogenesis
Amand, Mathieu; ERPICUM, Charlotte ULg; Gilles, Christine ULg et al

in Pulido, Rafael (Ed.) Protein Tyrosine Phosphatases: Methods and Protocols (in press)

Therapeutic perspectives targeting angiogenesis in cancer stimulated an intense investigation of the mechanisms triggering and governing angiogenic processes. Several publications have highlighted the ... [more ▼]

Therapeutic perspectives targeting angiogenesis in cancer stimulated an intense investigation of the mechanisms triggering and governing angiogenic processes. Several publications have highlighted the importance of typical dual-specificity phosphatases (DSPs) or MKPs in endothelial cells and their role in controlling different biological functions implicated in angiogenesis such as migration, proliferation, apoptosis, tubulogenesis and cell adhesion. However, among atypical DSPs, the only one investigated in angiogenesis was DUSP3. We recently identified this DSP as new key player in endothelial cells and angiogenesis. In this chapter we provide with detailed protocols and models used to investigate the role of DUSP3 in endothelial cells and angiogenesis. We start the chapter with an overview of the role of several DSPs in angiogenesis. We continue with providing a full description of a highly efficient transfection protocol to deplete DUSP3 using small interfering RNA (siRNA) in the primary Human Umbilical Vein Endothelial Cells (HUVEC). We next describe the major assays used to investigate different processes involved in angiogenesis such as tube formation assay, proliferation assay and spheroids sprouting assay. We finish the chapter by validating our results in DUSP3-knockout mice using in vivo angiogenesis assays such as Matrigel plug and Lewis lung carcinoma cell subcutaneous xenograft model followed by anti-CD31 immunofluorescence and ex vivo aortic ring assay. All methods described can be adapted to other phosphatases and signaling molecules. [less ▲]

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See detailDynamics of Internalization and Recycling of the Pro-Metastatic Membrane Type 4-Matrix Metalloproteinase (MT4-MMP) in Breast Cancer Cells
Truong, Alice ULg; Yip, Cassandre ULg; PAYE, Alexandra ULg et al

in FEBS Journal (2015)

MT4-MMP (MMP17) is a glycosylphosphatidyl inositol (GPI)-anchored membrane-type MMP expressed on the cell surface of human breast cancer cells. In triple negative breast cancer cells, MT4-MMP promotes ... [more ▼]

MT4-MMP (MMP17) is a glycosylphosphatidyl inositol (GPI)-anchored membrane-type MMP expressed on the cell surface of human breast cancer cells. In triple negative breast cancer cells, MT4-MMP promotes primary tumor growth and lung metastases. Although trafficking and internalization of the transmembrane MT1-MMP have been extensively investigated, little is known about the regulatory mechanisms of the GPI-anchored MT4-MMP. Here, we investigated the fate and cellular trafficking of MT4-MMP by analyzing its homophilic complex interactions, internalization and recycling dynamics compared to an inert form, MT4-MMP-E249A. Oligomeric and dimeric complexes were analyzed by co-transfection of cells with FLAG- or Myc-tagged MT4-MMP by reducing and non-reducing immunoblots and co-immunoprecipitation experiments. The trafficking of MT4-MMP was studied using an antibody feeding assay and confocal microscopy analysis or cell surface protein biotinylation and Western blot analysis. We demonstrate that MT4-MMP forms homophilic complexes at the cell surface, internalizes in early endosomes, and some of the enzyme is either auto-degraded or recycled to the cell surface. Our data indicate that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Although MT4-MMP localizes with caveolin-1, MT4-MMP internalization was not affected by inhibitors of caveolin-1 or clathrin endocytosis pathways but was reduced by cdc42 or RhoA silencing with siRNA. We provide a new mechanistic insight into the regulatory mechanisms of MT4-MMP, which may have implications in the design of novel therapeutic strategies for metastatic breast cancer. This article is protected by copyright. All rights reserved. [less ▲]

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See detailMT4-MMP, a potential prognostic factor in triple negative breast cancer
Yip, Cassandre ULg; FOIDART, Pierre ULg; SOMJA, Joan ULg et al

Scientific conference (2015, December 03)

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See detailFROM METABOLOMICS STUDY OF AGE RELATED MACULAR DEGENERATION (AMD) TO THE DEVELOPMENT OF NEW PDK INHIBITORS
Arslan, Deniz ULg; Schoumacher, Matthieu ULg; Pirotte, Bernard ULg et al

in Arslan, Deniz (Ed.) Gazi Pharma Symposium Abstract Book (2015, November 12)

Metabolomics is one of the most recent technologies in the Omics sciences defined as “the comprehensive characterization of small molecules (called metabolites) in different biological samples.” This ... [more ▼]

Metabolomics is one of the most recent technologies in the Omics sciences defined as “the comprehensive characterization of small molecules (called metabolites) in different biological samples.” This methodology can be applied in many areas, such as biomarker discovery, clinical studies, drug efficacy and toxicity evaluation, diagnostic tools, quality control or drug discovery. Its capability to extract biochemical information associated with a cellular or biological system makes this technique a powerful tool for Medicinal Chemistry. In this work, we present a 1H NMR metabolomics study applied to therapeutic target discovery. Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of the retina specialized for the high-acuity vision. Exudative AMD, called “wet”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, have demonstrated that lactate level is clearly involved in the severity of the pathology as well as the relationship between lactate, CNV and AMD. According to this result, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment opportunities in AMD disease. [less ▲]

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See detailDynamics of Internalization and Recycling of the pro-Metastatic Membrane Type 4-Matrix Metalloproteinase (MT4-MMP) in Breast Cancer cells
Truong, Alice ULg; Yip, Cassandre ULg; PAYE, Alexandra ULg et al

Poster (2015, October 26)

MT4-MMP (MMP17) is a glycosyl-phosphatidyl inositol-anchored membrane-type matrix metalloproteinase expressed at the cell surface of human breast cancer cells. In triple negative breast cancer, MT4-MMP ... [more ▼]

MT4-MMP (MMP17) is a glycosyl-phosphatidyl inositol-anchored membrane-type matrix metalloproteinase expressed at the cell surface of human breast cancer cells. In triple negative breast cancer, MT4-MMP promotes primary tumor growth and lung metastases. Recently, we demonstrated that EGFR activation and signaling are enhanced by MT4-MMP in a non-proteolytic dependent manner. While trafficking and internalization of EGFR was extensively investigated, little is known about MT4-MMP. Here, we investigated the dimerization, internalization and recycling dynamics of MT4-MMP and its mutated inactive form MT4-MMP-E249A. We demonstrate that MT4-MMP forms dimers and oligomers at the cell surface, a process that was not inhibited neither by broad-spectrum MMP inhibitors (GM6001 and BB94) nor TIMP-2. MT4-MMP is internalized in early endosomes from 10 minutes to 60 minutes. Once internalized, some amount of MT4-MMP is auto-degraded, whereas its inert form E249A was found intact. Large part of the internalized enzyme was recycled intact at the cell surface. By exploring its endocytosis, we found that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Overall, we provided a new mechanistic insight on the regulatory mechanisms of MT4-MMP in human breast cancer cells. We also, highlighted unique features of MT4-MMP among membrane-associated MMPs, which may be useful for the design of novel therapeutic strategies for metastatic breast cancer. [less ▲]

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See detailImplication of adamalysin proteases in mesothelioma
Sepult, Christelle ULg; Rocks, Natacha ULg; Bekaert, Sandrine et al

Conference (2015, September 30)

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See detailClinical significance of MT4-MMP and EGFR expression in Breast Cancer
Yip, Cassandre ULg; PAYE, Alexandra ULg; Truong, Alice ULg et al

Scientific conference (2015, September 11)

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See detailInvolvement of adamalysin proteases in modulations of tumor microenvironment and premetastatic niches.
Donati, Kim ULg; Bekaert, Sandrine; Sepult, Christelle ULg et al

Poster (2015, September)

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See detailMT4-MMP, a potential therapeutic target in triple negative breast cancer
Yip, Cassandre ULg; FOIDART, Pierre ULg; SOMJA, Joan ULg et al

Poster (2015, September)

MT4-MMP and EGFR axis may have a significant role in patient outcome and response to EGFR targeted therapy. This axis is clinically relevant in TNBC, the most aggressive breast cancer subtype. TNBC are ... [more ▼]

MT4-MMP and EGFR axis may have a significant role in patient outcome and response to EGFR targeted therapy. This axis is clinically relevant in TNBC, the most aggressive breast cancer subtype. TNBC are known to express high level of EGFR and treatment options are limited due to the non response of to the EGFR targeted therapy. Expression levels of MT4-MMP and EGFR in TNBC may be used as prognosis factor for the selection of patient who may respond or not to EGFR targeted therapy. Also, our data shed light and the potential therapeutic option of targeting both MT4-MMP and EGFR in TNBC. [less ▲]

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See detailIn vitro evaluation of an anti-apoptotic drug, Z-VAD-FMK, for further use in ovarian tissue transplantation
Fransolet, Maïté ULg; HENRY, Laurie ULg; LABIED, Soraya ULg et al

Poster (2015, June 14)

Study question: In a model reproducing early ischemia after ovarian tissue transplantation, does the pan-caspase inhibitor Z-VAD-FMK could prevent granulosa cell apoptosis? Summary answer: Results ... [more ▼]

Study question: In a model reproducing early ischemia after ovarian tissue transplantation, does the pan-caspase inhibitor Z-VAD-FMK could prevent granulosa cell apoptosis? Summary answer: Results obtained with HGL5 granulosa cell line suggest that Z-VAD-FMK is efficient to protect granulosa cells from etoposide or CoCl2 induced apoptosis. What is known already: Removal, cryopreservation and subsequent graft of ovarian strips after cancer treatment have been successfully used to re-establish female fertility. However, the pregnancy rate after autografting of cryopreserved tissue is about 30%. Indeed, the major problem after transplantation is follicular loss due to ischemic reperfusion injury. Study design, size, duration: Three human granulosa cell lines (GC1a, HGL5 and COV434) were cultured during 48h with Z-VAD-FMK with or without etoposide to induce apoptosis. To reproduce the ischemic phase of the graft, cells were cultured without serum under reduced O2 (1%) or with CoCl2 (chemical hypoxia). Participants/materials, setting, methods: Granulosa cells were used as a model since they are essential for oocyte survival. Metabolic cell activity was evaluated by the WST-1 assay. Cell apoptosis was analyzed by flow cytometry after annexin V-FITC and propidium iodide double staining. The mRNA levels and protein expression of apoptotic markers were evaluated using RT-qPCR and western blot analysis. Main results and the role of chance: Flow cytometry showed that cells co-treated with etoposide and Z-VAD-FMK displayed a higher percentage of viable cells as compared to etoposide alone. When in vivo ischemic stage was mimicked (1% O2), no beneficial effect of the Z-VAD-FMK was detected. However, a significant decrease of the number of early apoptotic cells was evidenced by flow cytometry for HGL5 cells treated with Z-VAD-FMK. RT-qPCR and western blot analysis revealed that apoptotic molecules were not modulated. Metabolic activity of the 3 cell lines was reduced by CoCl2. For HGL5 cells, this decrease was partially reversed by Z-VAD-FMK. The number of viable cells was reduced by CoCl2 in HGL5 cells but Z-VAD-FMK allowed to preserve a similar number of viable and apoptotic cells than in control condition. Limitations, reasons for caution: In this study we used 3 different cell lines but granulosa cells represent only a part of the cell types present in ovarian tissue biopsies. Experiences on the effect of Z-VAD-FMK on primary culture of granulosa cells have not yet been realized. Wider implications of the findings: This study suggests that the use of an antiapoptotic drug could be efficient to improve ovarian tissue transplantation outcomes. Ovarian tissue grafting studies using our xenograft murine model will be performed to test the potential efficacy of this drug to improve tissue viability and primordial follicles preservation after transplantation. [less ▲]

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See detailN-Hydroxy-6-(5-Nitro- Naphtalimide)-Hexanamide Inhibits Lysine Deacetylation, Mitigates Angiogenesis and Reduces Tumor Growth
Shankar, T.V. Shiva; Sulka, B.; Hubert, P. et al

in Journal of Cancer Sciences (2015), 2(1),

In this report, we present a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human ... [more ▼]

In this report, we present a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish). Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA). Finally, ES8 also reduced tumor growth in mouse models of small cell lung cancer. Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies. [less ▲]

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See detailClinical significance of MT4-MMP and EGFR expression in Breast Cancer
Yip, Cassandre ULg; PAYE, Alexandra ULg; Truong, Alice ULg et al

Scientific conference (2015, June)

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See detailGenetic depletion of the dual specificity protein phosphatase DUSP3 promotes LLC Lung tumour metastasis
Vandereyken, Maud ULg; Amand, Mathieu; Van Overmeire, Eva et al

Poster (2015, June)

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell ... [more ▼]

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell cycle regulation and is up-regulated in several human cancers. The physiological role of this phosphatase is, however, poorly understood. We have recently generated a DUSP3 knockout mouse by homologous recombination. The obtained mice have no spontaneous phenotype or pathology. However, DUSP3 deficiency prevented neo-vascularization of subcutaneously transplanted Matrigel plugs and Lung Lewis Carcinoma (LLC) tumours, suggesting an involvement of DUSP3 in tumour angiogenesis. Considering the importance of angiogenesis in metastatic formation, our study aimed to investigate the role of DUSP3 in metastatic dissemination. To do so, we used the LLC experimental metastasis model that shortcuts the intravasation/extravasation processes by injecting intravenously the LLC and the B16 (metastatic melanoma cell line) cells. Surprisingly, LLC, but not B16, lung metastasis developed twice faster in DUSP3-KO than WT mice. The enhanced LLC metastatic growth in DUSP3-/- mice was transferable to WT mice via DUSP3-/- bone marrow adoptive transfer, suggesting an involvement of the hematopoietic compartment in the observed phenotype. This was confirmed by a higher infiltration of neutrophils and macrophages in the lungs of DUSP3-KO compared to WT mice after LLC injection. This infiltration was correlated with higher expression of the chemokine receptor CCR2 in LLC-bearing DUSP3-KO lungs macrophages. Interestingly, LLC, but not B16 cells, were found to secrete high level of CCL2/MCP1, the CCR ligand chemokine. In line with this observation, we found that DUSP3-/- bone marrow derived-macrophages have a higher migration potential in response to LLC, but not B16, -conditionned medium. Altogether, our results suggest that DUSP3 plays an important role in metastatic dissemination/growth by a mechanism involving the control of CCR2-CCL2 chemoattraction axis in macrophages. [less ▲]

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See detailCombined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms
Gérard, Céline ULg; Mestdagt, Mélanie; Tskitishvili, Ekaterine ULg et al

in Oncotarget (2015)

Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a ... [more ▼]

Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms. [less ▲]

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See detailFunctional MRI for predicting metastatic spreading at the time of surgery after neoadjuvant radiotherapy
LALLEMAND, François ULg; Leroi, Natacha ULg; Bahri, Mohamed Ali ULg et al

Poster (2015, April)

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the ... [more ▼]

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the tumor downsizing. Some studies demonstrated that the timing of surgery and the RT schedule could influence tumor dissemination and subsequently patient overall survival. Our aim is to evaluate with functional MRI the impact of the radiation treatment on the tumor microenvironment and subsequently to determine the best timing to perform surgery for avoiding tumor spreading. [less ▲]

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