References of "Noël, Agnès"
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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 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 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 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 detailNovel 3D microscopy techniques and image analysis algorithms to study cancer-related in vitro spheroid models
Louis, Thomas ULiege; Bourgot, Isabelle ULiege; Primac, Irina ULiege et al

Poster (2019)

Recent progresses in 3D microscopy techniques revolutionise our way to study biological processes involved in cancer metastasis thanks to innovative imaging of biological models. In vitro spheroid model ... [more ▼]

Recent progresses in 3D microscopy techniques revolutionise our way to study biological processes involved in cancer metastasis thanks to innovative imaging of biological models. In vitro spheroid model consists in an aggregate of one or several cell types labelled using fluorescent dyes or constructs and embedded in fibrillar type I collagen matrix. Studying spheroid invasion properties involves the use of various microscopy techniques and the development of adapted processing and quantification algorithms. [less ▲]

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See detailEstetrol, a newly designated orphan drug, for attenuation of neonatal Hypoxic-Ischemic Encephalopathy (HIE)
Tskitishvili, Ekaterine ULiege; Pequeux, Christel ULiege; VIELLEVOYE, Renaud ULiege et al

Poster (2018, November 13)

Estetrol, a newly designated orphan drug, for attenuation of neonatal Hypoxic-Ischemic Encephalopathy (HIE) Ekaterine Tskitishvili1*, Christel Pequeux1, Renaud Viellevoye2, Michelle Nisolle3, Agnes Noël1 ... [more ▼]

Estetrol, a newly designated orphan drug, for attenuation of neonatal Hypoxic-Ischemic Encephalopathy (HIE) Ekaterine Tskitishvili1*, Christel Pequeux1, Renaud Viellevoye2, Michelle Nisolle3, Agnes Noël1 and Jean-Michel Foidart1 1Laboratory of Development Biology and Tumor, University of Liege, Liege, Belgium; 2Department of Pediatrics, University of Liege, Liege, Belgium; 3Department of Ob/Gyn, University of Liege, Liege, Belgium Estetrol (E4) is a fetal estrogen synthesized only during human pregnancy. We aimed to study its role in attenuation of neonatal HIE. In vitro we defined antioxidative and cell viability effects of E4 on primary hippocampal cell cultures in oxidative stress condition by using lactate dehydrogenase (LDH) activity and cell survival (MTS) assays. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for gray and white matter (MAP-2 and MBP), neurogenesis (DCX) and angiogenesis (VEGF) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and GFAP) were measured by ELISA. Our results demonstrate that E4 has significant antioxidative and cell survival properties along with neuroprotective and therapeutic effects. It decreases the early gray and white matter loss and promotes neuro- and angiogenesis in vivo. Combined use of E4 with other steroids does not have priority over the single use of E4. We also defined that E4's antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Treatment by E4 has no effects on body weight, brain weight or body temperature. E4 might become an important safe and physiological substance to treat neonatal HIE. Based on our data EMA granted orphan drug designation to E4. References 1.Tskitishvili E, Nisolle M, Munaut C, Pequeux C, Gerard C, Noel A, Foidart JM.Estetrol attenuates Neonatal Hypoxic-Ischemic brain injury. Exp Neurol 2014; 261:298-307. 2. Tskitishvili E , Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noel A, Foidart JM. Use of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury: to combine or not to combine? Oncotarget 2016; 7(23):33722-43. 3. Tskitishvili E,Viellevoye R, Gerard C, Pequeux C, Munaut C, Nisolle M, Noel A, Foidart JM. Neonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem. Références en Gynécologie Obstetrique. 2016 17;1-4 4. Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, Foidart JM. Estrogen receptors and estetrol-dependent neuroprotective actions: a pilot study. J Endocrinol. 2017; 232(1):85-95. 5.Foidart JM, Tskitishvili E. International patent application. Estrogenic components for use in the treatment of neurological disorders. [less ▲]

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See detailMetabolomics for the discovery of new therapeutic approach and personalized medicine: the case of exudative Age-related Macular Degeneration.
LAMBERT, Vincent ULiege; Schoumacher, Matthieu ULiege; Lecomte, Julie ULiege et al

Conference (2018, September 19)

. Introduction 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 ... [more ▼]

. Introduction 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, which is characterized by choroidal neovascularization (CNV)1. Treatment is mainly based on regular intra-vitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. 2. Approach Metabolomics provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotypes, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in target identification and in personalized medicine2. In order to study CNV occurrence and evolution and to get novel and innovative insights into AMD, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). Sera samples coming from 97 healthy volunteers and 95 exudative AMD patients have been collected during ophthalmic exams at the CHU of Liège. Patients were separated into bleeder AMD group (patients with AMD in bleeding phase) and non-bleeder AMD group (patients with non-bleeding AMD). The CNV mice model mimics the exudative phase of AMD and allows the dynamic study of CNV evolution. 3. Results Metabolomics approach applied to the human cohorts led to a separation between healthy and non-healthy patients as well as between bleeder and non-bleeder groups. Few metabolites are linked to this discrimination. Among those, lactate and lipoproteins profile emerge as the main key metabolites. Higher lactate level was detected in patients during bleeding phase while low-density lipoproteins (LDL) and very low density lipoproteins (VLDL) levels seems to be increased in AMD patients. In the mice model, metabolomics profiles varied according to CNV occurrence. In this case again, lactate and lipoproteins profile were related to this evolution. Pharmacological normalization of lactate levels by blocking pyruvate deshydrogenase kinase (PDK) or by modulating LDH activity in the mice model, inhibits CNV formation, Moreover, CNV inhibition by anti-angiogenic drugs led also to a reduction of systemic lactate level. 4. Discussion Mechanistically, we have demonstrated through a combination of NMR measurements (both 1D and 2D), pharmacological modulation and molecular biology approaches, that lactate, initially produced in the eyes then at the systemic level, plays a critical role in the onset of the inflammatory and angiogenic phases. Targeting lactate level by a modulation of PDK appears to be an alternative to intra-vitreal injection of anti-VEGF and a putative new therapeutic approach to reduce CNV progression. Moreover, changes in lipoproteins profile could also be correlated with AMD and CNV progression and then could be a nice marker of the progression of the pathology. A longitudinal patients follow-up during anti-VEGF treatment is currently running while MS-based targeted metabolomics and lipidomics studies are planned to validate and deepen our first findings. Altogether, we demonstrated that metabolomics is a suitable tool to deep insight into pathologies and to identify some metabolites as functional, traceable and targetable molecules that open new perspectives for optimizing and personalizing treatment and patient follow-up. References 1. Ambati, J., & Fowler, B. (2012). Mechanisms of age-related macular degeneration. Neuron, 75(1), 26–39. http://doi.org/10.1016/j.neuron.2012.06.018 2. Jacob, M., Lopata, A. L., Dasouki, M., & Abdel Rahman, A. M. (2017). Metabolomics toward personalized medicine. Mass Spectrometry Reviews, (September). http://doi.org/10.1002/mas.21548 [less ▲]

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See detailADAM28 deletion in mice impacts lung metastasis formation
Hubeau, Céline ULiege; Gerard, Catherine; Carnet, Oriane ULiege et al

Conference (2018, September 19)

ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. In addition, ADAM28 is thought to be an important regulator of ... [more ▼]

ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. In addition, ADAM28 is thought to be an important regulator of inflammatory signaling pathways as this protease shed the pro-inflammatory cytokine, pro-TNF-alpha. ADAM28 also interacts with integrins and a P-selectin ligand (PSGL-1) involved in inflammatory cell migration. All these findings suggest that ADAM28 contributes to cancer development and progression. This project aims to characterize the effects of host-derived ADAM28 on lung metastasis formation using an ADAM28-/- mouse model. Lewis Lung Carcinoma cells and B16K1 melanoma cells were intravenously injected in ADAM28-/- and wild-type (WT) mice. An unexpected increased tumor development was found in lungs of ADAM28-/- mice. As ADAM28 is associated with lymphocyte transendothelial migration, lymphocyte subtypes implicated in tumor cytotoxicity or in regulation of immune response were studied by flow cytometry. Results showed that less CD8+ T and NK cells were infiltrated within lungs of ADAM28-/- tumor-bearing mice as compared to WT mice. Moreover, less CD8+ T cells were counted within the spleen of naïve ADAM28-/- mice. These data were confirmed in a mouse model where 4T1 breast carcinoma cells were intravenously injected in ADAM28-/- BALB/c mice. Intrinsic properties of CD8+ T cells from ADAM28-/- mice were not affected by ADAM28 depletion as they were able to proliferate, to be activated and to migrate. Further investigations are required to explain the CD8+ T cell phenotype in ADAM28-deficient mice. Our results suggest a protective effect of ADAM28 derived from the host microenvironment by indirectly regulate the immune response. [less ▲]

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See detailTransgenerational effects of exposure to an EDC mixture on maternal behavior and sexual development
Lopez Rodriguez, David ULiege; Delli, Virginia; GERARD, Arlette ULiege et al

Conference (2018, July 17)

Environmental factors such as endocrine disrupting chemicals (EDCs) have been proven to produce transgenerational inherited modifications. A rising public health challenge is to determine the effect of ... [more ▼]

Environmental factors such as endocrine disrupting chemicals (EDCs) have been proven to produce transgenerational inherited modifications. A rising public health challenge is to determine the effect of complex mixtures of EDCs on the developing body throughout generations. In this study we aim to determine the transgenerational effects of a mixture of EDCs on female sexual development and behavior. 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. Sexual development (sex ratio, vaginal opening (VO), GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were measured from F0 to F3 generation. In utero exposed females (F1) when raising pups, showed an increased time resting alone and decreased time licking and grooming pups. F2 (animals whose germlines were exposed) and F3 exposed animals showed an altered sex ratio in favor of males and F2 and F3 females showed delayed VO. F2 and F3 females followed for estrous cyclicity showed significant alterations of estrous cyclicity characterized by a significant increase in the time spent in estrus and decreased time spent in diestrus. F3 females presented an increased GnRH interpulse interval compared to control. Overall, data shows that gestational exposure to an EDCs mixture can affect maternal behavior and sexual development during several generations. The effects observed in the F3 generation suggest the presence of transgenerational epigenetic mechanisms. [less ▲]

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See detailNMR-based Metabolomics for New Target Discovery and Personalized Medicine: Application to Age-Related Macular Degeneration (AMD).
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Leenders, Justine ULiege et al

Conference (2018, July 05)

Abstract: Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful ... [more ▼]

Abstract: Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful technological platform for metabolomics approach. Metabolomics is a growing area of the “omics” sciences and is defined as the comprehensive identification and quantification of lowmolecular weight metabolites in biological samples. It provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotype, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in new target identification and in personalized medicine. Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Treatment is mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. In order to study CNV occurrence and evolution and to get new and innovative insights into this pathology, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). This approach led us to identify some metabolites linked to CNV developments in both human and murine samples. These molecules could be considered not only as markers of the pathology but also as putative target for a new treatment of AMD. Among those, lactate emerges as a key metabolite in both settings. Mechanistically, we demonstrated that lactate, initially produced in the eyes increases at the systemic level and play a critical role in the onset of the inflammatory and angiogenic phases. For this purpose, we use a combination of NMR measurements (both 1D and 2D) and molecular biology approaches. The control of the systemic concentration of lactate by PDHK inhibition or by LDH modulation decreases significantly CNV development. Based on a metabolomics approach, our data support the innovative concept of lactate as a putative target for a new therapeutic approach of AMD as well as a useful marker for patient’s follow-up during treatment. We highlight also the utility and the efficacy of NMR for metabolomics and metabolites measurement in complex biological samples. [less ▲]

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See detailAnti-metastatic effect of ADAM28 derived from the microenvironment
Gérard, Catherine ULiege; Rocks, Natacha ULiege; Carnet, Oriane ULiege et al

Poster (2018, July 01)

Detailed reference viewed: 27 (10 ULiège)
See detailEffect of ADAM28 depletion on angiogenesis and lymphangiogenesis processes
Hubeau, Céline ULiege; Gerard, Catherine; Carnet, Oriane ULiege et al

Conference (2018, May 30)

Introduction ADAM28, a protease of the adamalysin family, is overexpressed by carcinoma cells in various cancers including non-small cell lung carcinoma (NSCLC) and breast cancer. In vivo studies reported ... [more ▼]

Introduction ADAM28, a protease of the adamalysin family, is overexpressed by carcinoma cells in various cancers including non-small cell lung carcinoma (NSCLC) and breast cancer. In vivo studies reported that knockdown of ADAM28 reduced primary tumor growth and lung metastatic formation suggesting a potential pro-tumoral role of ADAM28. Although cellular mechanism remain poorly described, ADAM28 is thought to stimulate angiogenesis and thus, promoting tumor progression. Indeed, ADAM28 can cleave CTGF from the CTGF/VEGF165 complex leading to the release of VEGF165. Another known substrate of ADAM28 is von Willebrand factor (vWF) which deficiency is associated with an increased angiogenesis and vasculature density. Therefore, we could hypothesize that ADAM28 induces angiogenesis through the cleavage of vWF. All these findings suggest that ADAM28 contributes to cancer development and progression by stimulating angiogenesis. Aim This project aims to investigate ADAM28 functions in the lung tumor microenvironment especially in the angiogenesis using an ADAM28 conditional knockout mouse model. Results Angiogenesis and lymphangiogenesis were assessed in lung metastasis of both ADAM28 KO and WT mice after intravenous injection of LLC cells. Immunofluorescence staining indicated that blood vessel density was increased within lung metastasis of WT mice as compared to ADAM28 KO mice. In contrast, lymphatic vessel density was similar between both groups. In addition, endothelial cell migration was evaluated in tumor-free mice using the ex vivo aortic ring assay. Result indicated that endothelial cells from ADAM28 KO mice migrated more than endothelial cells from WT mice. We also showed that blood vessel permeability was similar in WT and ADAM28 KO mice suggesting that ADAM28 depletion don’t affect blood vessel structure. Moreover, we assessed the expression of adhesion markers (ICAM-1, VCAM-1) and found no difference between both groups. Perspectives All these data need to be confirmed before drawing further conclusions. Indeed, we will confirm the increased blood vessel density in lung metastasis of WT mice using other tumor mouse models. It could also be interesting to evaluate angiogenesis in primary tumor of WT and ADAM28 KO mice. We will repeat the aortic ring experiment and perform immunostaining of pericytes and endothelial cells to study in more details the structure of the newly formed blood vessels. Angiogenesis and lymphangiogenesis will be investigated using different in vivo models such as the ear sponge assay and the corneal neovascularization model which are well-established in the laboratory. Furthermore, we would like to isolate endothelial cells from the lung of WT and ADAM28 KO mice to determine ADAM28 expression level in these cells and then, perform different in vitro assays (proliferation, migration, activation). [less ▲]

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See detailImplication of ADAM10 protease in malignant pleural mesothelioma
Bellefroid, Marine ULiege; Sepult, Christelle ULiege; Rocks, Natacha ULiege et al

Conference (2018, May 03)

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See detailTumor microenvironment modifications recorded with IVIM perfusion analysis after radiotherapy.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2018, April), 127(Supplement 1), 1285-1286

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

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates 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 clinical studies demonstrated that the timing of surgery and the RT schedule influence tumor dissemination and subsequently patient overall survival (Acta Oncol 2006). Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Oncotarget 2015). Here, we used functional MRI (fMRI) to record tumor microenvironment modifications after NeoRT. We aim to get non-invasive markers to establish the best timing to perform surgery and avoiding tumor spreading. Material and Methods Based on our NeoRT model, MDA-MB 231 and 4T1 cells were implanted in the flank of SCID and BalbC mice, respectively. We locally irradiated (PXI, X-Rad SmART) tumors with 2x5Gy and then surgically removed at different time points after RT. We acquired fMRI (9,4T Agilent) before and after RT. Diffusion Weighted (DW) - MRI was performed every 2 days between RT and surgery. For each tumor, 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 B-value (from 40 to 1000) and B0, in the 3 main directions. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results With the MDA-MB 231, we observed a significant and transient increase (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 modification. We observed similar results with 4T1 cells, where F increased at day 3 (55% of the basal value, n=10, p<0,05) then returned to initial level. The difference in timing for the peak of F (day 6 vs day 3) could be related to the difference in tumor growth according to the cell line (four weeks for MDA-MB 231 cells vs one week for 4T1 cells). We also observed a decrease of hypoxia (pimonidazole staining) when surgery was performed on the peak but vascular architecture was not affected. Moreover, performing surgery during F and D* peak, in the MDA-MB 231model, is associated with an increase of lung metastases: 115% and 187% compared to a surgery performed before or after the peak. Conclusion We demonstrated the feasibility of repetitive fMRI imaging in preclinical models after NeoRT. We showed a significant difference in perfusion-related parameters (D* and F) at a specific time point depending of tumor cells correlated with tumor metastases. We demonstrated the feasibility of Image Guided Surgery for decreasing tumor metastases after NeoRT. [less ▲]

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See detailBrain modifications after stereotactic radiotherapy recorded by Functional MRI.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2018, April), 127(Supplement 1), 582

Purpose or Objective Brain irradiation is commonly used in malignant diseases (i.e. metastases or Glioblastoma) and in benign diseases (i.e. meningioma, epilepsy, vestibular schwannoma or Parkinson ... [more ▼]

Purpose or Objective Brain irradiation is commonly used in malignant diseases (i.e. metastases or Glioblastoma) and in benign diseases (i.e. meningioma, epilepsy, vestibular schwannoma or Parkinson disease). The use of stereotactic radiosurgery (SRS) allows the administration of very high doses in a single fraction (e.g. 120Gy), in a small brain volume. After irradiation, morphological and functional cerebral changes occur depending on the total dose, dose per fraction and the irradiated brain volume. The aim of this work is to use f-MRI to record adult normal brain tissue modification after irradiation with different radiotherapy doses and schedules and to identify new parameters of brain radio-damages. Material and Methods With a dedicated small animal radiotherapy device allowing IGRT (PXI, X-Rad SmART), we specifically irradiated with a 2mm-collimator, mimicking SRS, a small part of adult brain mice (n=72), known to have no impact on vital function, with dose schedules: 1X20Gy, 3X10Gy, 4X5Gy and no RT as control. We imaged brain mice longitudinally with a dedicated 9.4-T MRI (Agilent). Imaging was realized once before as reference level and after irradiation every month for the first 6 months and every 3 months during one year. For each mouse we acquired 14 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. We performed T1-weighted, T2-weighted, T1-mapping, T2-mapping and DW-MRI. For DW-MRI, we performed Fast Spin Echo MultiSlice sequences, with 9 different B-value and B0 (from 20 to 1000). We performed IntraVoxel Incoherent Motion (IVIM) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor). Results Only mice irradiated with 120Gy showed brain modifications in T1 and T2 anatomic images and in T1 mapping, ADC, D and F but no changes were recorded in D* or T2 mapping. All these changes started 5 weeks after SRS and then stabilized after 7 weeks. The mean values for the control group were stable during the 5 months (ADC 0,73μm²/ms; D 0,66μm²/ms; F 4,67%, T1 1,25 sec). For the 120Gy group, values were significantly higher after 5 weeks (Δ = compared to the control group) with ADC 1,66μm²/ms (Δ=151%); D 1,37μm²/ms (Δ=107%); F 18,84% (Δ=303%); T1 1,99 sec (Δ=59%). No specific behaviour changes were observed during all the experiment. Conclusion In this work, we studied normal brain modifications after SRS therapy with anatomical and functional MRI. SRS doses and schedules in this work reflected those used in clinic for tumor treatment or functional SRS. We showed an increase of ADC value 5 weeks after one single dose of 120Gy, compared to normal brain tissue. These results are consistent with radio-necrosis. In addition, we highlighted an increase of IVIM parameters D and F and an increase of T1 mapping in radio-necrosis area. These results increase the numbers of MRI parameters that could be used for following brain damage after radiation. [less ▲]

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See detailAnalyse détaillée de la seconde version de l’avant-projet de Code du bien-être animal wallon. Lecture commentée au 21/03/2018 du Chapitre 8 (Expérimentation animale)
Drion, Pierre ULiege; Corhay, Albert ULiege; Haubruge, Eric ULiege et al

Report (2018)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984 et ses modifications, aujourd’hui, le projet de code pour la Région wallonne). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la Directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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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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