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

in Oncogene (2019)

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 ▲]

Detailed reference viewed: 59 (21 ULiège)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 58 (12 ULiège)
Full Text
Peer Reviewed
See detailThe functional diversity of Aurora kinases: a comprehensive review
Willems, Estelle ULiege; 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 ▲]

Detailed reference viewed: 25 (6 ULiège)
Full Text
Peer Reviewed
See detailPhosphatases and solid tumors: focus on glioblastoma initiation, progression and recurrences
Dedobbeleer, Matthias ULiege; Willems, Estelle ULiege; 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 ▲]

Detailed reference viewed: 47 (14 ULiège)
Full Text
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 ▲]

Detailed reference viewed: 48 (19 ULiège)
See detailGBM cells from the tumour mass versus the subventricular zone: molecular and functional characterisation
Di Gregorio, Marina ULiege; Willems, Estelle ULiege; 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 ▲]

Detailed reference viewed: 105 (20 ULiège)
Full Text
Peer Reviewed
See detailCXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone.
Goffart, Nicolas ULiege; Lombard, Arnaud; Lallemand, François ULiege et al

in Neuro-Oncology (2017), 19(1), 66-77

BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that ... [more ▼]

BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse. [less ▲]

Detailed reference viewed: 89 (29 ULiège)
Full Text
Peer Reviewed
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)

Detailed reference viewed: 89 (9 ULiège)
Full Text
See detailImplication of AurA kinase in GBM cells chemotaxis in response to the production of CXCL12 in the subventricular zones
Willems, Estelle ULiege; Dedobbeleer, Matthias ULiege; LOMBARD, Arnaud ULiege et al

Poster (2016, October 13)

Despite great improvement in standard therapies (i.e. surgery, radiotherapy and chemotherapy) of glioblastoma (GBM), the median survival rate is 15 months due to patient relapses. A major advance in the ... [more ▼]

Despite great improvement in standard therapies (i.e. surgery, radiotherapy and chemotherapy) of glioblastoma (GBM), the median survival rate is 15 months due to patient relapses. A major advance in the understanding of GBM recurrences has been the identification of GBM-initiating cells (GIC). GIC are thought to be deeply involved in GBM recurrences. Our lab designed a mouse model by grafting human GBM cells in the striatum. After the graft, we observed that tumors develop in the mouse striatum and that GIC specifically invade the subventricular zones (SVZ). SVZ are stem cells niches crucial for adult neurogenesis which seems particularly propitious for gliomagenesis since they are abundant in growth factors and permissive to proliferation. We therefore looked for soluble factors secreted by the SVZ environment and demonstrated that the local production of the CXCL12 chemokine in the SVZ is responsible for the GIC-directed migration. In this work, we aim to study the role GBM therapeutic resistance associated with the invasion of the SVZ. In this work, we identified a new actor of the CXCL12 pathway by the phosphoproteome analysis of U87MG cells stimulated with CXCL12: the mitotic kinase Aurora A (AurA) whose activity seems crucial for the CXCL12-dependent chemotaxis of GBM cells [less ▲]

Detailed reference viewed: 51 (8 ULiège)
Full Text
Peer Reviewed
See detailThe Unexpected Roles of Aurora A Kinase in Gliobastoma Recurrences
Willems, Estelle ULiege; LOMBARD, Arnaud ULiege; Dedobbeleer, Matthias ULiege et al

in Targeted Oncology (2016), 12

The main obstacle for the cure of glioblastoma (GBM) is systematic tumor recurrence after treatment. More than 90 % of GBM tumors are indeed recurrent within 5 years after diagnosis and treatment. We ... [more ▼]

The main obstacle for the cure of glioblastoma (GBM) is systematic tumor recurrence after treatment. More than 90 % of GBM tumors are indeed recurrent within 5 years after diagnosis and treatment. We urgently need new therapies to specifically address these deadly relapses. A major advance in the understanding of GBM recurrence is the identification of GBMInitiating Cells (GIC), characterized by their abilities for self-renewal, multilineage differentiation, and proliferation. It appears that these features of GIC could be modulated by the mitotic kinase Aurora A (AurA). Indeed, besides its role in mitosis, AurA has recently been identified to regulate alternative functions like cell polarity, asymmetric cell division, and epithelial to mesenchymal transition. All these properties may help explain GBM therapeutic resistance and recurrence. In this review, we make the hypothesis that AurA could significantly contribute to GBM recurrences and we focus on the possible roles of AurA in GIC. [less ▲]

Detailed reference viewed: 46 (19 ULiège)
Full Text
Peer Reviewed
See detailCXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone
Goffart, Nicolas; LOMBARD, Arnaud ULiege; Dedobbeleer, Matthias ULiege et al

in Neuro-Oncology (2016)

Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months despite multimodal therapy, due to systematic relapses. We previously demonstrated that GBM-initiating cells (GIC ... [more ▼]

Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months despite multimodal therapy, due to systematic relapses. We previously demonstrated that GBM-initiating cells (GIC) are able to escape the tumor mass and specifically colonize the sub-ventricular zone (SVZ) after experimental striatal xenotransplantation. Using the same approach, we demonstrated in vivo a higher survival rate of SVZ-nested GIC after irradiation and investigated the pathway implied. [less ▲]

Detailed reference viewed: 31 (3 ULiège)
Peer Reviewed
See detailRole of AurA in the CXCL12-signaling pathway in glioblastoma cells
Willems, Estelle ULiege; Dedobbeleer, Matthias ULiege; Goffart, nicolas et al

Poster (2016)

Detailed reference viewed: 7 (1 ULiège)