References of "Noël, Agnès"
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See detailPyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics
LAMBERT, Vincent ULiege; hansen, Sylvain; Schoumacher, Matthieu ULiege et al

in Journal of Molecular Medicine (2020)

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative ... [more ▼]

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. [less ▲]

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See detailLiposomes and drug-in-cyclodextrin-in-liposomes formulations encapsulating 17β-estradiol: an innovative drug delivery system that prevents the activation of the membrane-initiated steroid signaling (MISS) of estrogen receptor α
Gallez, Anne ULiege; Palazzo, Claudio ULiege; Blacher, Silvia ULiege et al

in International Journal of Pharmaceutics (2020), 573

The encapsulation into liposomes of several types of molecules presents the advantages to protect the activity of these molecules and to target specific tissues. Nevertheless, a major obstacle remains the ... [more ▼]

The encapsulation into liposomes of several types of molecules presents the advantages to protect the activity of these molecules and to target specific tissues. Nevertheless, a major obstacle remains the incomplete understanding of nano-bio interactions. Specifically, the impact that inclusion of drug into liposomes or of drug-in-cyclodextrin-in liposomes (DCL) could have on the molecular and cellular mechanism of drug action is largely unknown. As a proof of concept, we evaluated the impact of 17β-estradiol (E2) included into liposomes or DCL on estrogen receptor (ER)α signaling pathways. Indeed, ERα relays the pleiotropic actions of E2 in physiology and pathophysiology through two major pathways: (1) the genomic/nuclear effects associated to the transcriptional activity of the ERα and (2) the rapid/nongenomic/membrane-initiated steroid signaling (MISS) effects related to the induction of fast signaling pathways occurring when ERα is anchored to the plasma membrane. We evidenced that the inclusion of E2 into liposomes (Lipo-E2) or into DCL (DCL-E2) prevented the activation of the rapid/nongenomic/extranuclear/MISS pathway of ERα, while the activation of the genomic/nuclear pathway was maintained. These results support that Lipo-E2 and DCL-E2 could be a useful tool to delineate the complex molecular mechanisms associated to ERα. In conclusion, this study supports the notion that inclusion of drugs into liposomes or DCL could modify some specific pathways of their molecular and cellular mechanisms of action. These results emphasized that attention should be paid to nano-bio interactions induced by the use of nanovectors in medicine. [less ▲]

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See detailBRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
Coussy, F.; El-Botty, R.; Château-Joubert, S. et al

in Science Translational Medicine (2020), 12(532),

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast ... [more ▼]

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors. Copyright © 2020 The Authors, some rights reserved. [less ▲]

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See detailNew Insight into exudative Age-related Macular Degeneration (AMD): A Metabolomics Approach
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Conference (2019, December 11)

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal neovascularization (CNV) and results in complete loss of central vision acuity leading to severe visual impairment and legal blindness. Currently, AMD diagnosis relies on ophthalmologic exams and treatments of the exudative form using anti-angiogenic drugs targeting vascular endothelial growth factors (VEGF). Despite these advances, the identification of therapeutic treatments and related biomarkers are essentials. In this study, we applied a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine CNV experimental model that mimics the pathology angiogenesis’s development phase. Sera from controls and AMD patients (in active and non-active pathology’s phases) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. This approach allows differentiation between active and non-active AMD patients and between laser-induced and the control mice groups. Moreover, the discriminating spectral zones are the same in both human and mice’s models, leading to the emergence of putative biomarkers of the exudative AMD. Among those, lactate and lipoprotein emerges as a key metabolite in both settings. Here we suggest metabolomics as a novel option for patients’ follow-up and new therapeutical strategies targeting lactate metabolism for AMD. [less ▲]

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See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase (PDK) Inhibitors
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Noël, Agnès ULiege et al

Poster (2019, December 11)

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 zone of ... [more ▼]

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 zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, 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 wet 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, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, 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 for AMD disease. [less ▲]

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See detailImpact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression
Bourgot, Isabelle ULiege; Louis, Thomas ULiege; Kasabova, Mariana et al

Poster (2019, September 20)

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell ... [more ▼]

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the contribution of CAF-derived Ctsb to tumor progression is unknown. By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells. [less ▲]

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See detailImpact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression
Bourgot, Isabelle ULiege; Louis, Thomas; Kasabova, Mariana et al

Conference (2019, September 19)

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell ... [more ▼]

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the contribution of CAF-derived Ctsb to tumor progression is unknown. By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells. [less ▲]

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See detailMicroenvironment-derived ADAM28 impacts the onset of lung cancer
Hubeau, Céline ULiege; Gérard, Catherine ULiege; Carnet, Oriane ULiege et al

Poster (2019, September)

Background ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. Moreover, in vivo studies have shown that knockdown of ... [more ▼]

Background ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. Moreover, in vivo studies have shown that knockdown of ADAM28 in tumor cells decreased the primary tumor growth and formation of lung metastasis. Besides, ADAM28 is thought to be an important regulator of inflammatory signaling pathways as it sheds the pro-inflammatory cytokine, pro-TNF-alpha. ADAM28 protease also interacts with integrins and the P-selectin glycoprotein ligand-1 leading to inflammatory cell migration. Altogether, these findings suggest that ADAM28 contributes to cellular mechanisms leading to cancer development and progression. Methods This study aims to characterize the effects of microenvironment-derived ADAM28 on lung metastasis formation. To achieve this purpose, we generated ADAM28-/- mice into two different mouse strains (C57BL/6 and BALB/c). Lung metastatic dissemination was assessed in both ADAM28-/- and wild-type (WT) mice after intravenous injection of Lewis Lung Carcinoma cells, B16K1 melanoma cells or 4T1 breast carcinoma cells. As ADAM28 promotes leukocyte transendothelial migration, lymphocyte subtypes implicated in tumor cytotoxicity or in regulation of immune response were studied by flow cytometry. Results An unexpected increased tumor burden was found in lungs of ADAM28-/- mice as compared to WT mice. Flow cytometry analysis revealed that less CD8+ T were infiltrated within lungs of ADAM28-/- tumor-bearing mice. Moreover, a reduced CD8+ T cell population was observed in the spleen of naïve ADAM28-/- mice that is not caused by an impaired T cell maturation in the thymus. Ex vivo assays demonstrated that intrinsic properties of CD8+ T cells from ADAM28-/- mice were not affected by ADAM28 deficiency as their proliferation, migration and activation was similar. Besides, we found no expression of ADAM28 in isolated CD8+ T cells from the spleen of ADAM28-/- and WT mice. Therefore, we hypothesized that ADAM28 indirectly modulates the anti-tumor cytotoxic immune response. We also found that ADAM28 depletion is associated with a reduced infiltration of NK cell within lungs of ADAM28-/- tumor-bearing mice. Conclusion Our results demonstrate a protective effect of microenvironment-derived ADAM28 by regulating the tumor-associated immune response. [less ▲]

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See detailStromal integrin alpha11 regulates PDGFR-beta signaling and promotes breast cancer progression.
Primac, Irina ULiege; Maquoi, Erik ULiege; Blacher, Silvia ULiege et al

in Journal of Clinical Investigation (2019), 130

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying ... [more ▼]

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin alpha11-deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin alpha11 and PDGFRbeta was found at both transcriptional and histological levels in BC specimens. High stromal integrin alpha11/PDGFRbeta expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using five CAF subpopulations (one murine, four human) revealed that integrin alpha11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, integrin alpha11 pro-invasive activity relies on its ability to interact with PDGFRbeta in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a pro-invasive matricellular protein. Pharmacological inhibition of PDGFRbeta and JNK impaired tumor cell invasion induced by integrin alpha11-positive CAFs. Collectively, our study uncovers an integrin alpha11-positive subset of pro-tumoral CAFs that exploits PDGFRbeta/JNK signalling axis to promote tumor invasiveness in BC. [less ▲]

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See detailNew insight in Metabolomics based study of Age Related Macular Degeneration (AMD): Lipoprotein profile and patients follow-up
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Poster (2019, June 23)

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal neovascularization (CNV) and results in complete loss of central vision acuity leading to severe visual impairment and legal blindness. Currently, AMD diagnosis relies on ophthalmologic exams and treatments of the exudative form using anti-angiogenic drugs targeting vascular endothelial growth factors (VEGF). Despite these advances, the identification of therapeutic treatments and related biomarkers are essentials. In this study, we applied a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine CNV experimental model that mimics the pathology angiogenesis’s development phase. Sera from controls and AMD patients (in active and non-active pathology’s phases) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. This approach allows differentiation between active and non-active AMD patients and between laser-induced and the control mice groups. Moreover, the discriminating spectral zones are the same in both human and mice’s models, leading to the emergence of putative biomarkers of the exudative AMD. Among those, lipoprotein profile is interesting while some studies highlighted HDL cholesterol and oxidized LDL with early and para-inflammatory AMD stages. Our primary studies show similar evolution in lipoprotein profile through the different human and mice’ groups. These data suggest that investigate lipoprotein profile could be the turning point in the pathologic process’s comprehension occurring during the apparition and/or the development of pathologic CNV process. [less ▲]

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See detailOzone-primed neutrophils promote early steps of tumor cell metastasis to lungs by enhancing their NET production
Rocks, Natacha ULiege; Vanwinge, Céline ULiege; Radermecker, Coraline ULiege et al

in Thorax (2019), 0

Air pollution, including particulates and gazes such as ozone (O3), is detrimental for patient’s health and has repeatedly been correlated to increased morbidity and mortality in industrialized countries ... [more ▼]

Air pollution, including particulates and gazes such as ozone (O3), is detrimental for patient’s health and has repeatedly been correlated to increased morbidity and mortality in industrialized countries. Although studies have described a link between ambient particulate matter and increased lung cancer morbidity, no direct relation has yet been established between O3 exposure and metastatic dissemination to lungs. [less ▲]

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See detailNew insight in Metabolomics based study of Age Related Macular Degeneration (AMD): Lipoprotein profile and patients follow-up.
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Conference (2019, May 23)

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form of this ... [more ▼]

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form of this pathology, which is characterized by a choroidal neovascularization (CNV). Currently, diagnosis of AMD relies on ophthalmologic exams and treatments of the exudative form are based on the use of anti-angiogenic drug targeting vascular endothelial growth factors. Despite these advance, several clinical challenges have to be overcome. Among those, the identification of biomarkers that could allow to refine patient stratification, to follow disease progression and evaluate responses to treatment are mandatory. For this purpose, we decide to apply NMR-based metabolomics approach on both AMD patients and on a laser-induced murine choroidal neovascularization experimental model. In the clinical study, the metabolomics approach does not allow a complete differentiation between control and AMD patients. However, focusing only on AMD group, a clear-cut separation between active and non-active phases could be highlighted. In the mice model, discrimination between laser-induced and control mice occurs only when CNV is installed. In both human and animal studies, lactate and lipoprotein profile were identified as the main biomarkers. Mechanistically, we demonstrated that lactate, plays a critical role in the onset of the inflammatory and angiogenic phases and could be correlated with the CNV development. Then, controlling lactate level appears as a new therapeutic approach of AMD On the other hand, lipoprotein profile is of particular interest for patient follow-up. Indeed, evaluation of lipoprotein profile change trough a simple methods allowed us to establish clear modification of profiles according to the active or non-active status of the patient and to the induced or non-induced status of the mice. This work focuses on the lipoprotein profile and on the development of a methodology that could be used to characterize and compared the different profiles in the human and the mice studies. [less ▲]

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See detailTumor modifications recorded with IVIM and DCE-MRI after Neoadjuvant radiotherapy.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2019, April), 133(Supplement 1), 284-285

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor ... [more ▼]

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor microenvironment and could potentially impact distant metastases occurrence. Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Leroi et al. Oncotarget 2015). Here, we aim to identify by fMRI noninvasive markers reflecting NeoRT related tumor microenvironment modifications that could predict the best timing for performing surgery and avoiding tumor spreading. Material and Methods To briefly delineate the NeoRT model, MDA-MB 231 tumor cells implanted in the flank of SCID mice were locally irradiated with 2x5Gy when tumor reached 100mm3 and then surgically removed at different time points. We performed fMRI, Diffusion Weighted (DW) and Dynamic Contract enhancement (DCE) – MRI, before RT and every 2 days between RT and surgery. We acquired 8 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different Bvalue (from 40 to 1000) and B0. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed a T1 mapping with multiple TR and DCE acquisition with 200 repetitions of 3 sec each and gadolinium IV injection after 10 repetitions. We performed semi-quantitative analysis. We validated tumor perfusion by immunochemistry with injection of FITC-dextran IV 3 min before surgery and CD31 labelling. Human Ki67 was used for lung metastases labelling and quantification. Results After the tumor irradiation, we observed a significant and transient increase at day 6 (60% of the basal value (n=6, p<0,05)) of F and D* parameters related to perfusion. The other parameters of the DW-MRI, ADC and D presented no modifications. The sham irradiated tumors used as control showed no modifications of all fMRI parameters. At the same timing, 6 days post-radiotherapy, DCE-MRI significantly demonstrated a WhashinSlope (n=13, p<0,05) increase. Immunochemistry confirmed the increase of tumor perfusion when surgery is performed at day 6. The sham irradiated tumors never demonstrated such changes. Finally, when surgery is performed on tumor increased perfusion measured by fMRI, it demonstrated a burst of lung metastasis compared to the other timings. Conclusion We showed a significant difference in perfusion-related parameters with fMRI and immunochemistry at a specific time point after NeoRT. These modifications are correlated with an increase of metastasis spreading related to surgery procedure. These results open new perspectives in the personalized medicine and MRI guided surgery timing after NeoRT. [less ▲]

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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; Noël, Agnès ULiege et al

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

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes ... [more ▼]

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes, including embryogenesis, organogenesis, tissue regeneration, angiogenesis, wound healing, and inflammation. MT4-MMP (MMP17) presents unique characteristics compared to other members of the family in terms of sequence homology, substrate specificity, and internalization mode, suggesting distinct physiological and pathological functions. While the physiological functions of MT4-MMP are poorly understood, it has been involved in different pathological processes such as arthritis, cardiovascular disease, and cancer progression. The mt4-mmp transcript has been detected in a large diversity of cancers. The contribution of MT4-MMP to tumor development has been further investigated in gastric cancer, colon cancer, head and neck cancer, and more deeply in breast cancer. Given its contribution to different pathologies, particularly cancers, MT4-MMP represents an interesting therapeutic target. In this review, we examine its biological and structural properties, and we propose an overview of its physiological and pathological functions. [less ▲]

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See detailADAM10 mediates malignant pleural mesothelioma invasiveness
Sepult, Christelle ULiege; Bellefroid, Marine ULiege; Rocks, Natacha ULiege et al

in Oncogene (2019)

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and ... [more ▼]

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and mesothelioma development is very long, the local invasion of mesothelioma is very rapid leading to a mean survival of one year after diagnosis. ADAM10 (A Disintegrin And Metalloprotease) sheddase targets membrane-bound substrates and its overexpression is associated with progression in several cancers. However, nothing is known about ADAM10 implication in MPM. In this study, we demonstrated higher ADAM10 expression levels in human MPM as compared to control pleural samples and in human MPM cell line. This ADAM10 overexpression was also observed in murine MPM samples. Two mouse mesothelioma cell lines were used in this study including one primary cell line obtained by repeated asbestos fibre injections. We show, in vitro, that ADAM10 targeting through shRNA and pharmacological (GI254023X) approaches reduced drastically mesothelioma cell migration and invasion, as well as for human mesothelioma cells treated with siRNA targeting ADAM10. Moreover, ADAM10 downregulation in murine mesothelioma cells significantly impairs MPM progression in vivo after intrapleural cell injection. We also demonstrate that ADAM10 sheddase downregulation decreases the production of a soluble N-cadherin fragment through membrane N-cadherin, which stimulated mesothelioma cell migration. Taken together, we demonstrate that ADAM10 is overexpressed in MPM and takes part to MPM progression through the generation of N-cadherin fragment that stimulates mesothelioma cell migration. ADAM10 inhibition is worth considering as a therapeutic perspective in mesothelioma context. [less ▲]

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See detailEffects of exposure to an EDC mixture on the pubertal timing through a maternal behavioral epigenetic multigenerational transmission
Lopez Rodriguez, David ULiege; Delli, Virginia; GERARD, Arlette ULiege et al

Conference (2019)

Endocrine disrupting chemicals (EDCs) are today a rising public health challenge because of their ubiquity and presence in complex mixtures and their effects on the developing body throughout generations ... [more ▼]

Endocrine disrupting chemicals (EDCs) are today a rising public health challenge because of their ubiquity and presence in complex mixtures and their effects on the developing body throughout generations. We aim at studying the effect of a mixture of EDCs on female sexual development during 3 generations of females after exposure and determine whether an epigenetic hypothalamic mechanism is involved in those effects. Female rats were orally exposed from 2 weeks before gestation until weaning to corn oil or a mixture of 14 anti-androgenic and estrogenic EDCs at low doses (F0 generation). Sexual development (vaginal opening, GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were measured from F1 to F3 generation. An RNAseq was carry out using mediobasal hypothalamus from females at P21 from the F1 and F3 generation to decipher targets of the exposure, then validated by RT-PCR and studied for epigenetic modifications by ChIP. F2 and F3 females showed a delayed puberty (delayed VO) and a decrease in the percentage of females having regular estrous cycles, characterized by a significant increase in the time spent in estrus and decreased time spent in diestrus. A hypothalamic epigenetic mechanism is known to be involved in the onset of puberty. We have observed both transcriptional and histone epigenetic alterations in genes involved in estrogen (ESR1), glutamtergic (GRIN2Dà and dopamine (TH and DRD1) signaling as well as in glucocorticoid activity (NR3C1 and CRH), kisspeptin (KISS1) and oxytocin (OXT). We have as well observed that F1 females, exposed in utero, which shows a decrease in TH mRNA expression spent less time licking and more time resting alone. Those modifications on maternal behavior are known to be transmitted through generations. Overall, data shows that gestational exposure to an EDCs mixture can affect maternal behavior and sexual development during several generations. The F1 alteration of maternal behavior caused by in utero exposure to the mixture of EDCs trigger a multigenerational transmission of the phenotype and an induces an altered epigenetic reprogramming if the hypothalamus. [less ▲]

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See detailEDC mixture disrupts maternal behavior and the hypothalamic control of puberty transgenerationally through epigenetic mechanisms.
Lopez Rodriguez, David ULiege; Alwin, Carlos Francisco; GERARD, Arlette ULiege et al

Poster (2019)

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquity as complex mixtures. Our goal was to study the effect of an EDC mixture on female sexual development ... [more ▼]

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquity as complex mixtures. Our goal was to study the effect of an EDC mixture on female sexual development during 3 generations. Female rats (F0 generation) were orally exposed to a mixture of 13 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before gestation until weaning. The mixture was composed of plasticizers, fungicides/pesticides, UV filters, parabens and acetaminophen at doses representing human exposure. Sexual development (vaginal opening, GnRH interpulse-interval, estrous cyclicity and folliculogenesis) and maternal behavior were studied from F0 to F3 generations. At PND21, mediobasal hypothalamus of the F1 and F3 were removed for gene expression, histone modifications and DNA methylation analysis of target genes. F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycle, decreased GnRH interpulse interval and altered late stage folliculogenesis. F1 and F2 females showed decreased maternal licking behavior while spending more time resting alone. The phenotype was associated with transcriptional and epigenetic alterations of hypothalamic genes involved in reproductive competence and behavior like kisspeptin (Kiss1), oxytocin (Oxt), estrogen (Esr1), glutamate (Grin2d), dopamine signaling (Th) as well as glucocorticoid activity (Nr3c1 and Crh). We have found alterations in repressive (H3K27me3, H3K9me3) or active (H3K4me3, H3K9ac) histone marks concomitant with transcriptional activity. Overall, gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamic control of puberty. Such effects could be mediated by alterations of maternal behavior. [less ▲]

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See detailTransgenerational Effects of Exposure to an EDC Mixture on Maternal Behavior and Sexual Development
Lopez Rodriguez, David ULiege; Awylyn, Carlos Francisco; Sevrin, Elena ULiege et al

Conference (2019)

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Full Text
Peer Reviewed
See detailLymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling
Dubois, Charline; Rocks, Natacha ULiege; Blacher, Silvia ULiege et al

in Endocrine-Related Cancer (2019), 26(2), 201-216

Oestrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of oestrogens in lung cancer development is a pre-requisite to support the development of sex-based ... [more ▼]

Oestrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of oestrogens in lung cancer development is a pre-requisite to support the development of sex-based treatments and identify patients who could potentially benefit from anti-oestrogen treatments. In this study, we highlight the contribution of lymphatic and blood endothelia in the sex-dependent modulation of lung cancer. The orthotopic graft of syngeneic lung cancer cells into immunocompetent mice showed that lung tumours grow faster in female mice than in males. Moreover, oestradiol (E2) promoted tumour development, increased lymph/angiogenesis and VEGFA and bFGF levels in lung tumours of females through an oestrogen receptor (ER) alpha-dependent pathway. Furthermore, while treatment with ERb antagonist was inefficient, ERa antagonist (MPP) and tamoxifen decreased lung tumour volumes, altered blood and lymphatic vasculature and reduced VEGFA and bFGF levels in females, but not in males. Finally, the quantification of lymphatic and blood vasculature of lung adenocarcinoma biopsies from patients aged between 35 and 55 years revealed more extensive lymphangiogenesis and angiogenesis in tumour samples issued from women than from men. In conclusion, our findings highlight an E2/ERa-dependent modulation of lymphatic and blood vascular components of lung tumour microenvironment. Our study has potential clinical implication in a personalised medicine perspective by pointing to the importance of oestrogen status or supplementation on lung cancer development that should be considered to adapt therapeutic strategies. [less ▲]

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