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See detailConstruction of an oncolytic herpes virus (oHSV) for inducing apoptosis in glioblastoma: proof of concept
Sanchez Gil, Judith ULiege; Collignon, Alice; Lebrun, Marielle et al

Poster (2019, January 15)

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See detailDeciphering the response of subventricular zone-nested glioblastoma cells after surgery
LOMBARD, Arnaud ULiege; Dedobbeleer, Matthias ULiege; DEWANDRE, Quentin ULiege et al

Poster (2018, November)

INTRODUCTION: Glioblastoma (GBM) is the most frequent primary malignant brain tumor in adults, with really poor prognosis, subsequent to systematic recurrences, which occur in 80% of cases in the ... [more ▼]

INTRODUCTION: Glioblastoma (GBM) is the most frequent primary malignant brain tumor in adults, with really poor prognosis, subsequent to systematic recurrences, which occur in 80% of cases in the resection margin of initial tumor. We previously demonstrated that, after experimental striatal xenotransplantation, GBM cells, and particularly GBM-initiating cells (GIC), are able to escape the tumor mass and specifically colonize the sub-ventricular zone (SVZ), a well-known neurogenic zone in adult brains. We also demonstrated that this specific oriented migration is driven by a CXCL12-CXCR4 signalization. In this study, we address the potential implication of SVZ-nested tumor cells in local GBM relapses. MATERIALS AND METHODS: We engrafted in the right striatum of nude mice GBM cells (GB138) from a human primary culture, which are previously transfected with a lentiviral construction in order to express the RFP spontaneously, while they conditionally express eGFP, only in presence of Cre-recombinase. As the GB138 cells reach the SVZ, we injected in the lateral ventricle an Adeno-Associated Viral vector expressing Cre-recombinase, which is able to infect nearby GB138 cells. We finally compared 3 mice that were not operated (control group) with 3 mice that underwent tumor resection (surgery group) and quantify green spots in the tumor mass (TM) and/or resection cavity (RC) every 20 microns thanks to Clarity Lightsheet microscope. RESULTS: We found that the median of green spots for the 3 mice of the control group was respectively 1, 0 and 0 in TM, while the median for the surgery group was 7, 8 and 47 in RC. The Standard Deviation (SD) for the control group was respectively 1.1, 0.4 and 0.6, while SD for the surgery group was respectively 1.5, 1.7 and 16. CONCLUSION: SVZ-nested GBM cells seem to be recruited for tumor relapse after surgery. [less ▲]

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See detailCXCL12-loaded poly(lactic-co-glycolic) acid microspheres for the chemotactic recruitment of glioblastoma stem cells
Lumapat, Paul Noel ULiege; Garcia Fuentes, Marcos; Csaba, Noemi et al

Poster (2018, September 12)

INTRODUCTION Glioblastoma (GBM) stem cells (GSC) have been found to specifically migrate in response to a gradient of CXCL12 in a CXCR4-dependent manner1. This enables the escape of GSCs from the tumor ... [more ▼]

INTRODUCTION Glioblastoma (GBM) stem cells (GSC) have been found to specifically migrate in response to a gradient of CXCL12 in a CXCR4-dependent manner1. This enables the escape of GSCs from the tumor mass, potentially evading treatment and initiating metastases. We seek to take advantage of this mechanism for GBM therapy. By encapsulating CXCL12 in poly(lactic-co-glycolic) acid (PLGA) microspheres, we aim to create a polymeric platform capable of recruiting and directing migratory GSCs, thereby influencing GBM progression and metastasis formation. METHODS Human CXCL12 was initially complexated with heparin and poloxamine (Tetronic 1107)2. Resulting nanocomplexes were encapsulated in PLGA via emulsion solvent evaporation/extraction to form microspheres. Microspheres were characterized for morphology, encapsulation efficiency, and in vitro release characteristics. To verify promigratory activity, media preconditioned with blank and CXCL12-loaded microspheres were evaluated for chemotactic activity on U87MG GBM cells using a transwell migration assay. RESULTS AND DISCUSSION CXCL12-heparin nanocomplexes were successfully encapsulated in PLGA microspheres with diameter of 81.9±58.3 µm. The formulation had low initial burst release in vitro at <8%, and released >40% of the payload over a period of up to 90 days. Furthermore, media preconditioned with CXCL12-loaded microspheres for 1 to 8 weeks displayed promigratory activity towards GSCs. The number of migrating cells were 1.8- to 2.8-fold higher as compared to media preconditioned with blank microspheres. Treatment with AMD3100, a CXCR4 antagonist, abrogated this promigratory effect, indicating CXCR4 involvement. CONCLUSION The obtained results point to the potential of CXCL12-loaded microspheres for long-term recruitment of GSCs. These chemotactic microspheres, in combination with conventional and/or novel therapies, present a promising strategy for tackling GBM and its recurrence. [less ▲]

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See detailA simple and easy-to-implement SERS approach overcoming the nanoparticle stabilisation by serum proteins: application to dopamine and PC-12 cells
Dumont, Elodie ULiege; De Bleye, Charlotte ULiege; Cailletaud, Johan ULiege et al

Conference (2018, September 11)

This lecture presents the different steps regarding the development of a label-free SERS analytical method that was able to overcome the nanoparticle stabilisation caused by serum proteins. It relied on ... [more ▼]

This lecture presents the different steps regarding the development of a label-free SERS analytical method that was able to overcome the nanoparticle stabilisation caused by serum proteins. It relied on the pre-aggregation of the SERS substrate, which was a suspension of gold nanoparticles. Furthermore, several applications of the developed methodology were presented: the quantification of dopamine in the culture medium of rat phaeochromocytoma PC-12 cells as well as the influence of calcium, potassium and dexamethasone on dopamine exocytosis from these cells. [less ▲]

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See detailDevelopment of a SERS strategy to overcome the nanoparticle stabilisation effect in serum-containing samples: Application to the quantification of dopamine in the culture medium of PC-12 cells
Dumont, Elodie ULiege; De Bleye, Charlotte ULiege; Cailletaud, Johan ULiege et al

in Talanta (2018), 186

The analysis of serum samples by surface-enhanced Raman spectroscopy (SERS) has gained ground over the last years. However, the stabilisation of colloids by the proteins contained in these samples has ... [more ▼]

The analysis of serum samples by surface-enhanced Raman spectroscopy (SERS) has gained ground over the last years. However, the stabilisation of colloids by the proteins contained in these samples has restricted their use in common practice, unless antibodies or aptamers are used. Therefore, this work was dedicated to the development of a SERS methodology allowing the analysis of serum samples in a simple and easy-to-implement way. This approach was based on the pre-aggregation of the colloid with a salt solution. Gold nanoparticles (AuNPs) were used as the SERS substrate and, owing to its physiopathological importance, dopamine was chosen as a model to implement the SERS approach. The presence of this neurotransmitter could be determined in the concentration range 0.5 to 50 ppm (2.64 – 264 µM) in the culture medium of PC-12 cells, with a R² of 0.9874, and even at lower concentrations (0.25 ppm, 1.32 µM) in another matrix containing fewer proteins. Moreover, the effect of calcium and potassium on the dopamine exocytosis from PC-12 cells was studied. Calcium was shown to have a predominant and dose-dependent effect. Finally, PC-12 cells were exposed to dexamethasone in order to increase their biosynthesis and release of dopamine. This increase was monitored with the developed SERS approach. [less ▲]

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See detailDecrease in SV2A expression in the hippocampus involves changes in cognition and anxiety-like features.
Serrano Navacerrada, Maria Elisa ULiege; Bartholomé, Odile ULiege; Van Den Ackerveken, Priscilla ULiege et al

Poster (2018, July)

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose link with the epilepsy has been reported in multiples articles. However, the behavioral consequences of the decrease in its ... [more ▼]

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose link with the epilepsy has been reported in multiples articles. However, the behavioral consequences of the decrease in its expression remain still unclear. The purpose of our research is to better understand the role of this protein through the evaluation of cKO (Grik4 +/-, SV2A lox/lox) mice of both sexes, which present a specific decrease in the hippocampus. After a first evaluation of the SV2A levels in the hippocampus with the in vitro [18F]UCB-H autoradiography, differences in brain metabolism were assessed with [18F]FDG in mPET and ex vivo autoradiography. Finally, the phenotype of cKO mice was analyzed with a behavioral test battery. Our results showed a strong reduction of SV2A expression in the whole hippocampus of cKO mice, with regard to the WT mice, not accompanied by statistically significant differences in brain metabolism between groups, either in vivo or ex vivo. No statistically significant differences were found in spontaneous locomotor activity or fear-linked memory. However, cKO males showed significant more anxiety than WT (less percent of entries in open arms) and females presented spatial memory deficits measured in the Barnes Maze (less time spend in quadrant during the test). These results could explain the comorbidity between anxiety, memory impairment and epilepsy present both in animal models and in humans, suggesting an important role of SV2A in the symptomatology of other neurodegenerative diseases, such as the Alzheimer disease, or in anxiety-related pathologies. [less ▲]

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See detailFrom Neural Crest Development to Cancer and Vice Versa: How p75NTR and (Pro)neurotrophins Could Act on Cell Migration and Invasion?
Wislet, Sabine ULiege; Vandervelden, Geoffrey ULiege; Rogister, Bernard ULiege

in Frontiers in Molecular Neuroscience (2018), 11

The p75 neurotrophin receptor (p75NTR), also known as low-affinity nerve growth factor, belongs to the tumor necrosis factor family of receptors. p75NTR is widely expressed in the nervous system during ... [more ▼]

The p75 neurotrophin receptor (p75NTR), also known as low-affinity nerve growth factor, belongs to the tumor necrosis factor family of receptors. p75NTR is widely expressed in the nervous system during the development, as well as, in the neural crest population, since p75NTR has been described as ubiquitously expressed and considered as a neural crest marker. Neural crest cells (NCCs) constitute an transient population accurately migrating and invading, with precision, defined sites of the embryo. During migration, NCCs are guided along distinct migratory pathways by specialized molecules present in the extracellular matrix or on the surfaces of those cells. Two main processes direct NCC migration during the development: (1) an epithelial-to-mesenchymal transition and (2) a process known as contact inhibition of locomotion. In adults, p75NTR remains expressed by NCCs and has been identified in an increasing number of cancer cells. Nonetheless, the regulation of the expression of p75NTR and the underlying mechanisms in stem cell biology or cancer cells have not yet been sufficiently addressed. The main objective of this review is therefore to analyze elements of our actual knowledge regarding p75NTR roles during the development (mainly focusing on neural crest development) and see how we can transpose that information from development to cancer (and vice versa) to better understand the link between p75NTR and cell migration and invasion. In this review, we successively analyzed the molecular mechanisms of p75NTR when it interacts with several coreceptors and/or effectors. We then analyzed which signaling pathways are the most activated or linked to NCC migration during the development. Regarding cancer, we analyzed the described molecular pathways underlying cancer cell migration when p75NTR was correlated to cancer cell migration and invasion. From those diverse sources of information, we finally summarized potential molecular mechanisms underlying p75NTR activation in cell migration and invasion that could lead to new research areas to develop new therapeutic protocols. © 2018 Wislet, Vandervelden and Rogister. [less ▲]

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailThe functional diversity of Aurora kinases: a comprehensive review
Willems, Estelle; Dedobbeleer, Matthias ULiege; Di Gregorio, Marina ULiege et al

in Cell Division (2018)

Aurora kinases are serine/threonine kinases essential for the onset and progression of mitosis. Aurora members share a similar protein structure and kinase activity, but exhibit distinct cellular and ... [more ▼]

Aurora kinases are serine/threonine kinases essential for the onset and progression of mitosis. Aurora members share a similar protein structure and kinase activity, but exhibit distinct cellular and subcellular localization. AurA favors the G2/M transition by promoting centrosome maturation and mitotic spindle assembly. AurB and AurC are chromosome-passenger complex proteins, crucial for chromosome binding to kinetochores and segregation of chromosomes. Cellular distribution of AurB is ubiquitous, while AurC expression is mainly restricted to meiotically-active germ cells. In human tumors, all Aurora kinase members play oncogenic roles related to their mitotic activity and promote cancer cell survival and proliferation. Furthermore, AurA plays tumor-promoting roles unrelated to mitosis, including tumor stemness, epithelial-to-mesenchymal transition and invasion. In this review, we aim to understand the functional interplay of Aurora kinases in various types of human cells, including tumor cells. The understanding of the functional diversity of Aurora kinases could help to evaluate their relevance as potential therapeutic targets in cancer. [less ▲]

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See detailAurora A plays a dual role in migration and survival of human glioblastoma cells according to the CXCL12 concentration
Willems, Estelle; Dedobbeleer, Matthias ULiege; Di Gregorio, Marina ULiege et al

in Oncogene (2018)

Primary glioblastoma is the most frequent human brain tumor in adults and is generally fatal due to tumor recurrence. We previously demonstrated that glioblastoma-initiating cells invade the ... [more ▼]

Primary glioblastoma is the most frequent human brain tumor in adults and is generally fatal due to tumor recurrence. We previously demonstrated that glioblastoma-initiating cells invade the subventricular zones and promote their radio-resistance in response to the local release of the CXCL12 chemokine. In this work, we show that the mitotic Aurora A kinase (AurA) is activated through the CXCL12–CXCR4 pathway in an ERK1/2-dependent manner. Moreover, the CXCL12–ERK1/ 2 signaling induces the expression of Ajuba, the main cofactor of AurA, which allows the auto-phosphorylation of AurA. We show that AurA contributes to glioblastoma cell survival, radio-resistance, self-renewal, and proliferation regardless of the exogenous stimulation with CXCL12. On the other hand, AurA triggers the CXCL12-mediated migration of glioblastoma cells in vitro as well as the invasion of the subventricular zone in xenograft experiments. Moreover, AurA regulates cytoskeletal proteins (i.e., Actin and Vimentin) and favors the pro-migratory activity of the Rho-GTPase CDC42 in response to CXCL12. Altogether, these results show that AurA, a well-known kinase of the mitotic machinery, may play alternative roles in human glioblastoma according to the CXCL12 concentration. [less ▲]

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See detailPhosphatases and solid tumors: focus on glioblastoma initiation, progression and recurrences
Dedobbeleer, Matthias ULiege; Willems, Estelle; Freeman, Stephen ULiege et al

in Biochemical Journal (2017), 474(17), 2903-2924

Phosphatases and cancer have been related for many years now, as these enzymes regulate key cellular functions, including cell survival, migration, differentiation and proliferation. Dysfunctions or ... [more ▼]

Phosphatases and cancer have been related for many years now, as these enzymes regulate key cellular functions, including cell survival, migration, differentiation and proliferation. Dysfunctions or mutations affecting these enzymes have been demonstrated to be key factors for oncogenesis. The aim of this review is to shed light on the role of four different phosphatases (PTEN, PP2A, CDC25 and DUSP1) in five different solid tumors (breast cancer, lung cancer, pancreatic cancer, prostate cancer and ovarian cancer), in order to better understand the most frequent and aggressive primary cancer of the central nervous system, glioblastoma. [less ▲]

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See detailDiscovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines
Schnekenburger, M; Goffin, Eric ULiege; Lee, J-Y et al

in Journal of Medicinal Chemistry (2017), 60(11), 4714-4733

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting ... [more ▼]

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors. [less ▲]

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See detailPuzzling Out Synaptic Vesicle 2 Family Members Functions
Bartholomé, Odile ULiege; Van Den Ackerveken, Priscilla ULiege; Sanchez Gil, Judit ULiege et al

in Frontiers in Molecular Neuroscience (2017)

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See detailThe Radioprotective role of MKP1 in GBM cells
Dedobbeleer, Matthias ULiege; Willems, Estelle ULiege; Di Gregorio, Marina ULiege et al

Poster (2017, May 19)

In patients with glioblastoma multiform (GBM), recurrenceis the rule despite continuous advances in surgery, radio-and chemotherapy. Within these most frequent primary brain tumors, glioblastoma stem ... [more ▼]

In patients with glioblastoma multiform (GBM), recurrenceis the rule despite continuous advances in surgery, radio-and chemotherapy. Within these most frequent primary brain tumors, glioblastoma stem cells or initiating cells (GIC) have recently been described and were shown to be involved in these recurrences. Our lab recently demonstrated that GIC, once injected into the striatum of immunodeficient nude mice, exhibit a tropism for the subventricular zones (SVZ), one of the adult neurogenic niches bringing them an appropriate molecular and cellular environment to growth. After irradiation of these mice, we still discovered cells inside the SVZ. We then questionned the role of the CXCL12/CXCR4 pathway in radioprotection phenotype. After demonstrating that CXCL12 could play a radioprotectiverole, we wanted to know by which mechanism it happens. Knowing that MKP1, the major regulator of the MAP kinase pathway, shown a higher phosphorylation profile after CXXL12 stimulation, and that this protein is involve in many cancers and that its role in glioblamstoma remain unclear, we wanted to know could have a radioprotectiverole link or not to the CXCL12/CXCR4 signalling pathway [less ▲]

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See detailGBM cells from the tumour mass versus the subventricular zone: molecular and functional characterisation
Di Gregorio, Marina ULiege; willems, Estelle; Dedobbeleer, Matthias ULiege et al

Poster (2017, May)

Life expectancy after diagnosis of glioblastoma (GBM) remains poor even with the best available treatment. This catastrophic survival is the direct consequence of systematic tumour recurrence. It has ... [more ▼]

Life expectancy after diagnosis of glioblastoma (GBM) remains poor even with the best available treatment. This catastrophic survival is the direct consequence of systematic tumour recurrence. It has previously been demonstrated that the subventricular zone (SVZ, a neurogenic niche of the adult central nervous system) attracts and harbours GBM cells, expressing stem cell biomarkers that act like glioblastoma-initiating cells. These cells hosted in the SVZ may be responsible for tumour recurrence. To better understand the difference between cells from the tumour mass (TM) and those migrating to the SVZ, this project will focus on two axes. First, a proteomic and transcriptomic approach will be used to identify one or more biomarkers that might help to establish if recurrences originate from the TM or the SVZ. The second aim of the project is to compare these two populations of cells from a functional point of view. Some functional differences have already been observed: cells derived from SVZ form more spheroids than those derived from TM (1). U87MG cells from SVZ also form tumours more easily in mice compared to cells derived from the TM (2). However, preliminary results in chemo- and radioresistance assays on the cultured cells (U87MG) do not show significant differences between the two populations. Therefore, it might be the SVZ environment that plays a key role in therapeutic resistance, rather than intrinsic biological differences of cells from the TM versus the SVZ. [less ▲]

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See detailThe unexpected role of Aurora A kinase in glioblastoma recurrences
Willems, Estelle ULiege; LOMBARD, Arnaud ULiege; Dedobbeleer, Matthias ULiege et al

in Targeted Oncology (2017)

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See detailHuman bone marrow harbors cells with neural crest-associated characteristics like human adipose and dermis tissues.
Coste, Cécile; Neirinckx, Virginie ULiege; Sharma, Anil et al

in PLoS ONE (2017), 12(7), 0177962

Adult neural crest stem-derived cells (NCSC) are of extraordinary high plasticity and promising candidates for use in regenerative medicine. Several locations such as skin, adipose tissue, dental pulp or ... [more ▼]

Adult neural crest stem-derived cells (NCSC) are of extraordinary high plasticity and promising candidates for use in regenerative medicine. Several locations such as skin, adipose tissue, dental pulp or bone marrow have been described in rodent, as sources of NCSC. However, very little information is available concerning their correspondence in human tissues, and more precisely for human bone marrow. The main objective of this study was therefore to characterize NCSC from adult human bone marrow. In this purpose, we compared human bone marrow stromal cells to human adipose tissue and dermis, already described for containing NCSC. We performed comparative analyses in terms of gene and protein expression as well as functional characterizations. It appeared that human bone marrow, similarly to adipose tissue and dermis, contains NESTIN+ / SOX9+ / TWIST+ / SLUG+ / P75NTR+ / BRN3A+/ MSI1+/ SNAIL1+ cells and were able to differentiate into melanocytes, Schwann cells and neurons. Moreover, when injected into chicken embryos, all those cells were able to migrate and follow endogenous neural crest migration pathways. Altogether, the phenotypic characterization and migration abilities strongly suggest the presence of neural crest-derived cells in human adult bone marrow. [less ▲]

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