References of "Bellahcene, Akeila"
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See detailTGFBI, an ECM interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration
Costanza, Brunella; Rademaker, Gilles ULiege; Tiamiou, Assia ULiege et al

in International Journal of Cancer (2019)

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC ... [more ▼]

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high TGFBI expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates FAK signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic ECM interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies. [less ▲]

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See detailHuman colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis.
Rademaker, Gilles ULiege; Costanza, Brunella; Bellier, Justine ULiege et al

in Oncogenesis (2019)

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use ... [more ▼]

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use of glycolysis to produce energy. Recent studies demonstrated that mitochondrial electron transport chain inhibitor reduced colon cancer tumour growth. Accumulating evidence show that myoferlin, a member of the ferlin family, is highly expressed in several cancer types, where it acts as a tumour-promoter and participates in the metabolic rewiring towards oxidative metabolism. In this study, we showed that myoferlin expression in colon cancer lesions is associated with low patient survival and is higher than in non-tumoural adjacent tissue. Human colon cancer cells silenced for myoferlin exhibit a reduced oxidative phosphorylation activity associated with mitochondrial fission leading, ROS accumulation, decreased cell growth, and increased apoptosis. We observed the triggering of a DNA damage response culminating to a cell cycle arrest in wild-type p53 cells. The use of a p53 null cell line or a compound able to restore p53 activity (Prima-1) reverted the effects induced by myoferlin silencing, confirming the involvement of p53. The recent identification of a compound interacting with a myoferlin C2 domain and bearing anti-cancer potency identifies, together with our demonstration, this protein as a suitable new therapeutic target in colon cancer. [less ▲]

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See detailMethylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer
Nokin, Marie-Julie ULiege; Bellier, Justine ULiege; Durieux, Florence et al

in Breast Cancer Research (2019), 21(1

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See detailMethylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer
Bellier, Justine ULiege; Nokin, Marie-Julie ULiege; Lardé, Eva ULiege et al

in Diabetes Research and Clinical Practice (2019)

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See detailMyoferlin controls mitochondrial structure and metabolism in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness.
Rademaker, Gilles ULiege; Hennequière, Vincent; Brohée, Laura et al

Poster (2018, July 01)

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on classical chemotherapies. Cell fraction can survive to the chemotherapy and is responsible for tumor relapse. It appears that these cells rely on oxydative phosphorylation (OXPHOS) for survival. Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer. In the present study, we discovered that myoferlin was more expressed in cell lines undergoing (OXPHOS) than in glycolytic cell lines. In the former cell lines, we showed that myoferlin silencing reduced OXPHOS activity and forced cells to switch to glycolysis. The decrease in OXPHOS activity is associated with mitochondrial condensation and network disorganization. An increase of Dynamin-related protein (DRP)-1 phosphorylation in myoferlin-depleted cells led us to suggest mitochondrial fission, reducing cell proliferation, ATP production and inducing autophagy and ROS accumulation. Electron microscopy observation revealed mitophagy, suggesting mitochondrial alterations. To confirm the clinical importance of myoferlin in PDAC, we showed that low myoferlin expression was significantly correlated to high overall survival. Myoferlin staining of PDAC sections was negatively correlated with several 18FDG PET indices indicating that glycolytic lesions had less myoferlin. These observations are fully in accordance with our in vitro data. As the mitochondrial function was associated with cell chemoresistance, the metabolic switch induced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies. Among them, targeting functional domains (C2, Dysf, …) of myoferlin should be a priority. [less ▲]

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See detailMyoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Nokin, Marie-Julie ULiege et al

in Oncogene (2018)

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism. [less ▲]

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See detailMurine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases
Blomme, A.; van Simaeys, G.; Doumont, G. et al

in Oncogene (2018), 37(9), 1237-1250

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine ... [more ▼]

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations. Metabolic signatures of cancer cells and stroma were measured separately by MALDI-imaging, while metabolite changes in entire tumors were quantified using mass spectrometry approach. Measurement of glucose metabolism was also conducted in vivo using [18F]-fluorodeoxyglucose (FDG) and positron emission tomography (PET). In CRC/CRC-LM PDX model, human stroma was entirely replaced at the second generation. Despite this change, MALDI-imaging demonstrated that the metabolic profiles of both stromal and cancer cells remained stable for at least four generations in comparison to the original patient material. On the tumor level, profiles of 86 water-soluble metabolites as well as 93 lipid mediators underlined the functional stability of the PDX model. In vivo PET measurement of glucose uptake (reflecting tumor glucose metabolism) supported the ex vivo observations. Our data show for the first time that CRC/CRC-LM PDX model maintains the functional stability at the metabolic level despite the early replacement of the human stroma by murine cells. The findings demonstrate that human cancer cells actively educate murine stromal cells during PDX development to adopt the human-like phenotype. © 2017 Macmillan Publishers Limited, part of Springer Nature [less ▲]

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See detailInnovative methodology for the identification of soluble biomarkers in fresh tissues.
Costanza, Brunella ULiege; Turtoi, Anders; Bellahcene, Akeila ULiege et al

in Oncotarget (2018), 9(12), 10665-10680

The identification of diagnostic and prognostic biomarkers from early lesions, measurable in liquid biopsies remains a major challenge, particularly in oncology. Fresh human material of high quality is ... [more ▼]

The identification of diagnostic and prognostic biomarkers from early lesions, measurable in liquid biopsies remains a major challenge, particularly in oncology. Fresh human material of high quality is required for biomarker discovery but is often not available when it is totally required for clinical pathology investigation. Hence, all OMICs studies are done on residual and less clinically relevant biological samples. Here after, we present an innovative, simple, and non-destructive, procedure named EXPEL that uses rapid, pressure-assisted, interstitial fluid extrusion, preserving the specimen for full routine clinical pathology investigation. In the meantime, the technique allows a comprehensive OMICs analysis (proteins, metabolites, miRNAs and DNA). As proof of concept, we have applied EXPEL on freshly collected human colorectal cancer and liver metastases tissues. We demonstrate that the procedure efficiently allows the extraction, within a few minutes, of a wide variety of biomolecules holding diagnostic and prognostic potential while keeping both tissue morphology and antigenicity unaltered. Our method enables, for the first time, both clinicians and scientists to explore identical clinical material regardless of its origin and size, which has a major positive impact on translation to the clinic. [less ▲]

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See detailMyoferlin controls mitochondrial structure in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Brohée, Laura ULiege et al

Poster (2017, September 22)

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on classical chemotherapies. Cell fraction can survive to the chemotherapy and is responsible for tumor relapse. It appears that these cells rely on OXPHOS for survival. Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer. In the present study, we discovered that myoferlin was more expressed in cell lines undergoing oxidative phosphorylation (OXPHOS) than in glycolytic cell lines. In the former cell lines, we showed that myoferlin silencing reduced OXPHOS activity and forced cells to switch to glycolysis. The decrease in OXPHOS activity is associated with mitochondrial network disorganization. Dynamin-related protein (DRP)-1 phosphorylation led us to suggest mitochondrial fission, reducing cell proliferation, ATP production and inducing autophagy and ROS accumulation. To confirm the clinical importance of myoferlin in PDAC, we showed that low myoferlin expression was significantly correlated to high overall survival. Myoferlin staining of PDAC sections was negatively correlated with several 18FDG PET indices indicating that glycolytic lesions had less myoferlin. As the mitochondrial function is demonstrated to enhance the cell resistance to the treatment, the metabolic switch forced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies. [less ▲]

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See detailMyoferlin, a new autophagy player in pancreatic cancer cells
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Peixoto, Paul et al

Poster (2017, February 01)

Despite intensive research, Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the deadliest forms of cancer. Early-stage of the disease is clinically silent and the diagnosis of the disease is mostly ... [more ▼]

Despite intensive research, Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the deadliest forms of cancer. Early-stage of the disease is clinically silent and the diagnosis of the disease is mostly made at an advanced stage. This late diagnosis contributes to one of the lowest 5-year survival rates (<5%). Today, PDAC are treated by surgery and/or adjuvant therapy, increasing only slightly the median survival of the patients. There is therefore an urgent need to develop new effective therapies for PDAC patients. PDAC are characterized by a high autophagic activity involved in its chemoresistance. Recently, key regulatory proteins controlling the metabolic reprogramming of PDAC cells were identified. By governing both autophagic flux and lysosomal catabolism, these proteins support the efficient processing of cargo from autophagy, providing PDAC cells with access to critical sources of nutrients. Interestingly, the high autophagy level in PDAC correlates with a poor patient outcome. Myoferlin, a member of the ferlin family overexpressed at protein level in different cancer types including PDAC, is a transmembrane protein able to bound to phospholipids and described to play an important function in membrane fusion. This characteristic invited us to investigate whether myoferlin could participate to autophagy, a process involving membrane fusion. Panc-1 cell line was used as a model of PDAC basal autophagy. Myoferlin expression was silenced using interfering RNA technology. Autophagosome abundance was evaluated by LC3-II western-blot and flow cytometry. Results indicated a significant increase in autophagosome abundance 48 h after myoferlin-silencing. This increase could arise from an increase of autophagy initiation or from an inhibition of autolysosome degradation. Using autophagy inhibitors, autophagic flux was evaluated by LC3-II and p62 western-blot after myoferlin-silencing. Results suggested a blockade in the autophagic process, impairing termination and autophagosome degradation by lysosome activity. Knowing the affinity of myoferlin for phospholipids, we wonder if this protein could interact with the phosphatidylethanolamine-conjugated LC3-II protein. Proximity-ligation assay suggested a close interaction between myoferlin and LC3. These results evoke an unexplored and undescribed role for myoferlin in autophagy. Understanding the involvement of myoferlin in this rediscovered biological process could give new clues in the development of new therapeutic strategy. [less ▲]

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See detailHormetic potential of methylglyoxal, a side-product of glycolysis, in switching tumours from growth to death.
Nokin, Marie-Julie ULiege; Durieux, Florence; Bellier, Justine ULiege et al

in Scientific Reports (2017), 7(1), 11722

Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly ... [more ▼]

Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG-mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth. [less ▲]

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See detailMethylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer.
Chiavarina, Barbara ULiege; Nokin, Marie-Julie ULiege; Bellier, Justine ULiege et al

in International Journal of Molecular Sciences (2017), 18(1),

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and ... [more ▼]

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression. [less ▲]

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See detailANTICANCER, ANTIPLASMODIAL AND ANTITRYPANOSOMAL ACTIVITIES OF CRUDE EXTRACTS OF PLATANUS ORIENTALIS
Ebralidze, L.; Mskhiladze, Lasha; Ledoux, Allison ULiege et al

in World Journal of Pharmaceutical Research (2017), 6(3), 170-175

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See detailMyoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes
Blomme, Arnaud; Fahmy, Karim; Peulen, Olivier ULiege et al

in Oncotarget (2016)

Exosomes are communication mediators participating in the intercellular exchange of proteins, metabolites and nucleic acids. Recent studies have demonstrated that exosomes are characterized by a unique ... [more ▼]

Exosomes are communication mediators participating in the intercellular exchange of proteins, metabolites and nucleic acids. Recent studies have demonstrated that exosomes are characterized by a unique proteomic composition that is distinct from the cellular one. The mechanisms responsible for determining the proteome content of the exosomes remain however obscure. In the current study we employ ultrastructural approach to validate a novel exosomal protein myoferlin. This is a multiple C2-domain containing protein, known for its conserved physiological function in endocytosis and vesicle fusion biology. Emerging studies demonstrate that myoferlin is frequently overexpressed in cancer, where it promotes cancer cell migration and invasion. Our data expand these ndings by showing that myoferlin is a general component of cancer cell derived exosomes from different breast and pancreatic cancer cell lines. Using proteomic analysis, we demonstrate for the rst time that myoferlin depletion in cancer cells leads to a signi cantly modulated exosomal protein load. Such myoferlin-depleted exosomes were also functionally de cient as shown by their reduced capacity to transfer nucleic acids to human endothelial cells (HUVEC). Beyond this, myoferlin-depleted cancer exosomes also had a signi cantly reduced ability to induce migration and proliferation of HUVEC. The present study highlights myoferlin as a new functional player in exosome biology, calling for novel strategies to target this emerging oncogene in human cancer. [less ▲]

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See detailMyoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer
Blomme, Arnaud; Costanza, Brunella ULiege; De Tullio, Pascal ULiege et al

in Oncogene (2016)

Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as ... [more ▼]

Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients. [less ▲]

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See detailNew role of osteopontin in DNA repair and impact on human glioblastoma radiosensitivity
Henry, Aurélie ULiege; Nokin, Marie-Julie ULiege; Leroi, Natacha ULiege et al

in Oncotarget (2016)

Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness ... [more ▼]

Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness characters and tumorigenicity of glioma initiating cells. Consultation of publicly available TCGA database indicated that high OPN expression correlated with poor survival in GBM patients. In this study, we explored the role of OPN in GBM radioresistance using an OPN-depletion strategy in U87-MG, U87-MG vIII and U251-MG human GBM cell lines. Clonogenic experiments showed that OPN-depleted GBM cells were sensitized to irradiation. In comet assays, these cells displayed higher amounts of unrepaired DNA fragments post-irradiation when compared to control. We next evaluated the phosphorylation of key markers of DNA double-strand break repair pathway. Activating phosphorylation of H2AX, ATM and 53BP1 was signi cantly decreased in OPN-de cient cells. The addition of recombinant OPN prior to irradiation rescued phospho-H2AX foci formation thus establishing a new link between DNA repair and OPN expression in GBM cells. Finally, OPN knockdown improved mice survival and induced a signi cant reduction of heterotopic human GBM xenograft when combined with radiotherapy. This study reveals a new function of OPN in DNA damage repair process post-irradiation thus further con rming its major role in GBM aggressive disease. [less ▲]

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See detailOsteopontin predicts radiotherapy response of glioblastoma patients : new role in DNA damage repair
Henry, Aurélie ULiege; Nokin, Marie-Julie; Leroi, Natacha ULiege et al

Conference (2016, March 22)

- Introduction: Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These ... [more ▼]

- Introduction: Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These treatments include maximal surgical resection, radiotherapy and concomitant or adjuvant chemotherapy with Temozolomide. However, the prognosis of adult patients with GBM remains poor and the survival outcome after treatment does not exceed 15 months. GBM-composing cells have developed many strategies to counteract these current therapies. Among the wide hallmarks acquired to survive, high osteopontin (OPN) expression correlates with lower overall and disease-free/relapse-free survival in all tumors combined, as well in brain cancer. Our recent study (Lamour V and Henry A, IJC 2015) has demonstrated the role of OPN in the tumorigenicity of glioblastoma cells and its importance in the maintenance of the stem characters. In the continuation of this work, our recent studies focused on the potential role of OPN in the resistance of GBM cells to radiotherapy and its potential implication in the initiation of Double Strand Breaks (DSBs) repair mechanisms. - Aims: In the context of this study, different GBM cell lines (U251-MG, U87-MG and U87 Viii) were used to assess the role of OPN in the initiation of the DSBs repair mechanism after an exposure to gamma-irradiation. - Methods and results: We performed the transient transfection of different GBM cell lines (U251-MG, U87-MG and U87-MG overexpressing EGFR VIII) with siRNAs specifically directed against OPN. After irradiation, all these OPN-depleted cells consistently showed a lower induction of γ–H2AX compared to control (irrelevant siRNA) as evidenced by western blot and immunofluorescence techniques. Thereafter, clonogenic assays allowed to prove that the survival of OPN-depleted cells was affected after an exposure to irradiation. To assess the importance of OPN expression in the response to radiotherapy, an heterotopic xenograft model was used. In brief, IPTG-inducible U87 shOPN clones were injected subcutaneously in NOD-SCID mice and were allowed to form a tumor. When average tumor volume reached a predetermined size range, mice were treated (or not) with IPTG by intraperitoneal injection during five days. At the end of the treatment, tumors were selectively exposed to gamma-irradiation by using a small animal irradiator X-RAD 225Cx (Precision X-Ray Inc., North Branford, CT). One week later, mice were sacrificed and tumors were measured. In this pilot study, we observed that mice in which the tumor was depleted in OPN displayed a slight regression in the tumor growth compared to mice that received radiotherapy alone (no IPTG), where the tumor volume remained constant. - Conclusions: Taken together, these preliminary data meet the fact that OPN is important in the response of GBM to radiotherapy. The in vitro results converge to the fact that OPN might be implicated in the initiation of the DSBs repair following irradiation. Currently, we would like to investigate this hypothesis in vivo but also to check the effect of OPN depletion combined to radiotherapy on the survival of mice in an orthotopic xenograft model. [less ▲]

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See detailEXPEL: A Novel Non-Destructive Method for Mining Soluble Tumor Biomarkers
Costanza, Brunella ULiege; Blomme, A; Bellahcene, Akeila ULiege et al

in Acta Gastro-Enterologica Belgica (2016), 79(1), 11

Detailed reference viewed: 60 (22 ULiège)