References of "Sounni, Nor Eddine"
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See detailMT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases
Yip, Cassandre ULiege; FOIDART, Pierre ULiege; Noel, Agnes et al

in International Journal of Molecular Sciences (2019), 20 (2)

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See detailExpression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy.
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

in Clinical Cancer Research (2019)

Abstract Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived ... [more ▼]

Abstract Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB).Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib + palbociclib) treatments.Results: EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone.Conclusions: We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy. [less ▲]

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See detailMetabolic adaptation to anti-angiogenic therapy
Sounni, Nor Eddine ULiege

Conference (2018, October 15)

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See detailMetabolic adaptation of tumor to hypoxia induced by anti-angiogenic therapy
Sounni, Nor Eddine ULiege

Conference (2018, March 16)

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See detailMT4-MMP, EGFR and RB expressions are predictive biomarkers of response to Erlotinib-Palbociclib combination in TNBC
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

Conference (2018, February 24)

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See detailExpression of MT4-MMP, EGFR and Rb in triple negative breast cancers strongly sensitizes tumors to Erlotinib and Palbociclib combination therapy
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

Scientific conference (2018, January 27)

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastasis. The standard systemic treatment relies entirely on chemotherapy. While ... [more ▼]

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastasis. The standard systemic treatment relies entirely on chemotherapy. While epidermal growth factor receptor (EGFR) is frequently over-expressed in TNBC, targeted therapies against EGFR did not show clinical benefit. Recently, we demonstrated that EGFR interacts with MT4-MMP, the membrane-type 4 matrix metalloproteinase in TNBC. Also, based on an immunohistochemistry (IHC) analysis we reported that EGFR and MT4-MMP are co-expressed in 79 % of human TNBC samples. Here, we identified MT4-MMP/EGFR axis as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein (Rb) inactivation. Finally, we investigated the significance of targeting EGFR and CDK4 in TNBC expressing MT4-MMP and EGFR. [less ▲]

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See detailMicroenvironment-derived ADAM28 prevents cancer dissemination
Gérard, Catherine ULiege; Hubeau, Céline ULiege; Carnet, Oriane ULiege et al

in Oncotarget (2018), 9(98), 37185-37199

Previous studies have linked cancer cell-associated ADAM28 expression with tumor progression and metastatic dissemination. However, the role of host-derived ADAM28 in cancer dissemination processes ... [more ▼]

Previous studies have linked cancer cell-associated ADAM28 expression with tumor progression and metastatic dissemination. However, the role of host-derived ADAM28 in cancer dissemination processes remains unclear. Genetically engineered-mice fully deficient for ADAM28 unexpectedly display increased lung colonization by pulmonary, melanoma or breast tumor cells. In experimental tumor cell dissemination models, host ADAM28 deficiency is further associated with a decreased lung infiltration by CD8+ T lymphocytes. Notably, naive ADAM28-deficient mice already display a drastic reduction of CD8+ T cells in spleen which is further observed in lungs. Interestingly, ex vivo CD8+ T cell characterization revealed that ADAM28-deficiency does not impact proliferation, migration nor activation of CD8+ T cells. Our data highlight a functional role of ADAM28 in T cell mobilization and point to an unexpected protective role for host ADAM28 against metastasis. [less ▲]

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See detailCapecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers.
Marangoni, Elisabetta; Laurent, Cecile; Coussy, Florence et al

in Clinical Cancer Research (2018)

PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to ... [more ▼]

PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. EXPERIMENTAL DESIGN: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. RESULTS: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naive derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. CONCLUSIONS: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response. [less ▲]

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See detailDusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner
Vandereyken, Maud; Jacques, Sophie ULiege; Van Overmeire, Eva et al

in PLoS ONE (2017)

Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion ... [more ▼]

Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel out- growth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice devel- oped larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour- promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the pres- ence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demon- strates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs. [less ▲]

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See detailCancer associated fibroblast-derived integrin α11 regulates PDGFRβ signaling to promote breast cancer progression
Primac, Irina ULiege; Blacher, Silvia ULiege; cimino, Jonathan et al

Conference (2017, April 24)

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by ... [more ▼]

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by mesenchymal cells and is correlated with fibroblast activation and matrix reorganization. While the role of ITGA11 in wound healing has been well described, only a very limited number of reports have assessed its role in the cancer disease. This research project aims to investigate the role of stromal ITGA11 in breast cancer. To analyze the in vivo effects of ITGA11 on tumor insurgence, growth and metastasis, we crossed the oncogenic MMTv-PyMT mice with the ITGA11 KO/WT mice, which develop spontaneously breast tumors. ITGA11 deletion strongly delayed tumor growth and metastasis in PyMT mouse model. ITGA11 was poorly expressed at early stages of the tumor progression and its expression was strongly increased in the late stage invasive carcinomas. Importantly, a reduced angiogenesis and collagen content was observed in tumors lacking of ITGA11. Furthermore, a strong co-localization between ITGA11 and PDGFRb, but not other CAF markers such as alpha smooth actin, was also observed within the tumor stroma, suggesting that ITGA11 defines a subpopulation of CAFs, which is not represented by myofibroblasts, but rather PDGFRb+ CAFs. For mechanistic investigation, CAFs and breast cancer cells were isolated from the PyMT model. ITGA11 co-immunoprecipitated with PDGFRb in the isolated CAFs and regulated its phosphorylation. Interestingly, ITGA11-deficient CAFs failed to promote CAF and cancer cell invasion, in contrast to WT CAFs in a spheroid invasion assay. A high throughput comparative proteomics analysis on CAF spheroids in 3D a system was next performed. Proteomics data identified several proteins with relevance in the cancer disease which were significantly modulated in CAFs through ITGA11 down-regulation. The top-ranking candidates are under validation and molecular pathways, which may link these targets and ITGA11 will be further analyzed in the in vitro models. Overall, these in vivo and in vitro data show that ITGA11 defines a PDGFRβ+ subpopulation of CAFs distinct from α-SMA+ myofibroblasts that promote tumor cell invasion and angiogenesis at late stages of carcinoma evolution. ITGA11 is a promising target within the stroma of breast cancer and further investigations of its molecular signaling pathways will be of great relevance. [less ▲]

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See detailMT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib.
Yip, Cassandre ULiege; Foidart, Pierre ULiege; Somja, Joan ULiege et al

in British Journal of Cancer (2017)

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a ... [more ▼]

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. METHODS: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. RESULTS: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. CONCLUSIONS: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.British Journal of Cancer advance online publication 14 February 2017; doi:10.1038/bjc.2017.23 www.bjcancer.com. [less ▲]

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See detailTumor host-interface in metastatic dissemination and adaptation to treatment
Sounni, Nor Eddine ULiege

Scientific conference (2017)

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See detailMetabolic adaptation to anti-angiogenic therapy, 3rd International Meeting on Cancer and Blood Vessels
Sounni, Nor Eddine ULiege

Scientific conference (2016, October 20)

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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 ULiege; Yip, Cassandre ULiege; PAYE, Alexandra ULiege et al

in FEBS Journal (2016), 283(4), 704-22

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 detailLipid metabolism in cancer: energy source for survival or biomass building blocks
Sounni, Nor Eddine ULiege

Scientific conference (2016)

Detailed reference viewed: 76 (2 ULiège)