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See detailLimited impact of imatinib in a murine model of sclerodermatous chronic graft-versus-host disease (scl-cGVHD)
Fransolet, Gilles ULg; Belle, Ludovic; SOMJA, Joan ULg et al

Conference (2016, December 08)

- Introduction: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD ... [more ▼]

- Introduction: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD develop the sclerodermatous form of the disease characterized by multiple organ fibrosis and loss of skin elasticity. Several studies have shown the potential benefits of imatinib, a tyrosine kinase inhibitor (TKI), as a treatment of fibrosis in cGVHD due to its ability to inhibit simultaneously PDGF-R and c-Abl pathways which are both involved in fibrosis mechanisms. - Aims: Some early-phase clinical studies have assessed the impact of TKIs in patients with steroid-refractory cGVHD. Unfortunately, these studies yielded to conflicting results underlying the importance of re-assessing the impact of imatinib in scl-cGVHD pre-clinical models. This work investigates the possible benefits of imatinib on fibrosis in a murine model of sclerodermatous chronic GVHD (scl-cGVHD). - Methods and results: Lethally irradiated Balb/cJ mice (7 Gy TBI) were injected i.v. with 1.106 or 10.106 bone marrow cells and 2.106 or 70.106 splenocytes from B10.D2 donnor mice (Moderate and Classical scl-cGVHD models respectively). Mice were then treated with sterile water or imatinib (150 mg/kg/day) by oral gavage from day +7 to day +52 following transplantation. cGVHD severity was assessed three times/week with a scoring system encompassing 5 criteria (mice posture, weight loss, activity, hair loss, skin integrity ; 0-1-2 point(s)/criteria). Skin biopsies were performed on day +29 following transplantation to assess phosphorylation of c-Abl (TGF-β pathway) and PDGF receptor. Our results show that imatinib failed to prevent/improve GVHD with a similar evolution of the GVHD severity with no differences between groups (neither in moderate cGVHD model, nor in the classical cGVHD model). Mice weight loss during the experiments was also comparable between groups in both models of cGVHD. In the classical model, histological analyses indicate a significant reduction of the phosphorylation level of the PDGR receptor (p = 0.0079). In vivo cell proliferation assay with CFSE were also performed and showed a reduced proliferation of T cells and subsets (CD4, CD8 and Tregs) in spleen, lymph nodes, bone marrow and blood after imatinib treatment. Finally, FACS analyses performed on days +21 and +35 after transplantation did not show any differences in the absolute T-cell counts. - Conclusions: Although we have observed a decreased phosphorylation level of PDGR receptor and less proliferation of T cells and subsets in vivo, imatinib failed to alleviate scl-cGVHD both in moderate and classical murine models of scl-cGVHD. [less ▲]

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See detailLimited impact of imatinib in a murine model of sclerodermic chronic graft-versus-host disease
Belle, Ludovic; Fransolet, Gilles ULg; SOMJA, Joan ULg et al

Poster (2016, November 17)

Background: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD develop ... [more ▼]

Background: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD develop the sclerodermatous form of the disease characterized by multiple organ fibrosis and loss of skin elasticity. Several studies have shown the potential benefits of imatinib, a tyrosine kinase inhibitor, as a treatment of fibrosis in cGVHD due to its ability to inhibit simultaneously PDGF-R and c-Abl pathways which are both involved in fibrosis mechanisms. This work investigates the possible benefits of imatinib on fibrosis in a murine model of sclerodermatous chronic GVHD (sclcGVHD). Methods: Lethally irradiated Balb/cJ mice (7 Gy TBI) were injected i.v. with 10.106 bone marrow cells and 70.106 splenocytes from B10.D2 donnor mice. Mice were then treated with sterile water or imatinib (150 mg/kg/day) by oral gavage from day +7 to day +52 following transplantation. GVHD severity was assessed three times/week with a scoring system encompassing 5 criteria (mice posture, weight loss, activity, hair loss, skin integrity ; 0-1-2 point(s)/criteria). Results: Our results show that imatinib failed to prevent/improve GVHD with a similar evolution of the GVHD severity with no differences between groups. Histological analyses indicate a significant reduction of the phosphorylation level of the PDGR receptor (p = 0,033) and a trend to a decreased level of phosphorylated c-Abl (p = 0,1854). In vivo cell proliferation assay with CFSE were also performed and showed a reduced proliferation of T cells and subsets (CD4, CD8 and Tregs) in spleen, lymph nodes, bone marrow and blood after imatinib treatment. Finally, FACS analyses performed on days +21 and +35 after transplantation did not show any differences in the absolute T-cell counts. Conclusion: Although we have observed a decreased phosphorylation level of PDGR receptor and less proliferation of T cells and subsets in vivo, imatinib failed to alleviate scl-cGVHD in a murine model of severe scl-cGVHD. [less ▲]

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See detailMyoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer
Blomme, Arnaud; Costanza, Brunella ULg; De Tullio, Pascal ULg 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 ULg; Nokin, Marie-Julie ULg; Leroi, Natacha ULg 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 detailPEGylation of lipoplexes: The right balance between cytotoxicity and siRNA effectiveness
Lechanteur, Anna ULg; Furst, Tania ULg; Evrard, Brigitte ULg et al

in European Journal of Pharmaceutical Sciences (2016), 93

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See detailAzacytidine mitigates experimental sclerodermic chronic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

in Journal of Hematology & Oncology (2016), 9

Background <br />Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express ... [more ▼]

Background <br />Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4+ T cells (CD4+Tconvs) but demethylated in Tregs. <br />Methods <br />Here, we assessed the impact of azacytidine (AZA) on cGVHD in a well-established murine model of sclerodermic cGVHD (B10.D2 (H-2d) → BALB/cJ (H-2d)). <br />Results <br />The administration of AZA every 48 h from day +10 to day +30 at the dose of 0.5 mg/kg or 2 mg/kg mitigated chronic GVHD. Further, AZA-treated mice exhibited higher blood and thymic Treg frequencies on day +35, as well as higher demethylation levels of the Foxp3 enhancer and the IL-2 promoter in splenocytes at day +52. Interestingly, Tregs from AZA-treated mice expressed more frequently the activation marker CD103 on day +52. AZA-treated mice had also lower counts of CD4+Tconvs and CD8+ T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4+Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells. <br />Conclusions <br />Our results indicate that AZA prevented sclerodermic cGVHD in a well-established murine model of cGVHD. These data might serve as the basis for a pilot study of AZA administration for cGVHD prevention in patients at high risk for cGVHD. [less ▲]

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See detailMALDI-imaging guided microproteomics workflow for biomarker discovery of intra-tumor heterogeneity
Alberts, Deborah ULg; Longuespée, Rémi ULg; Smargiasso, Nicolas ULg et al

Poster (2016, June 09)

Introduction A single tumoral tissue can bear phenotypically different cell populations. This phenomenon called intra-tumor heterogeneity can lead to differential behaviors regarding metastasis seeding ... [more ▼]

Introduction A single tumoral tissue can bear phenotypically different cell populations. This phenomenon called intra-tumor heterogeneity can lead to differential behaviors regarding metastasis seeding and therapy resistance [Zardavas et al., Nature Rev. Clin. Onc. 2015]. MALDI imaging has proven its efficiency for revealing hidden molecular features offering an insight into distinct cellular regions based on their molecular content. Further, proteomics applied to these regions could allow depicting the molecular context associated to particular cells groups and enable the collection of qualitative, quantitative and spatial information for each protein. Methods Breast cancer Formalin Fixed and Paraffin Embedded tissues, from patients whose outcome had been recorded over a period of 10 years, were provided by the department of Pathology of University of Liège. After Citric Acid Antigen Retrieval and trypsin digestion, images were obtained by MALDI-TOF/TOF-MS (Bruker, Germany). From the obtained datasets, segmentation and analytical data analysis were applied using SCiLS (Bruker, Germany) and the cloud software Multimaging (ImaBiotech, France). Small tissue areas were obtained by laser microdissection (LEICA LMD 700, Germany), upon which a combination of chemical processes was applied to ensure optimal protein antigen retrieval, extraction and digestion. Finally, the tissue pieces obtained were analyzed by LC-MS/MS using UPLC Waters Nanoacquity and Thermo Q-Exactive instruments. Preliminary data Based on mathematical calculations for the MALDI imaging datasets of the breast cancer FFPE tissues, Regions Of Interest (ROIs) were detected in a single tumor, revealing intra-tumoral heterogeneity, which can be correlated to the level of aggressiveness of the affliction and to the final prognosis of the patient. We aimed to compare the proteomic profiles of each of the small ROIs. Until today, proteomics applied to tissues composed by a restricted number of cells is quite tedious due to possible tissue losses during their handling. Recently, Longuespée [Longuespée et al., Methods 2015] published a method in order to retrieve the identification of 1400 proteins from microdissected tissue pieces containing only 2700 cells. This whole procedure allowed us to identify a panel of protein that characterizes tissue heterogeneity within a single tumor. This proves the applicability of the combination of MALDI imaging for the discovery of intra-tumoral heterogeneity without a priori, on a mathematical basis, and classical proteomics applied on laser-microdissected tissue samples of very restricted areas. This method will now be applied to several MALDI datasets in order to retrieve commune ROIs and to associate their presence with the information of each patient, such as their prognosis. Those ROIs will then be microdissected and subjected to microproteomic methods that will allow us to retrieve the extensive molecular context associated to bad patient prognosis and/or therapy resistance. The possibility to identify protein/peptide markers will have the power to predict the outcome of the breast cancer patient at the beginning of their treatment, and thus, improve the clinical care for the benefit of the patients. Novel aspect The workflow combines the unique advantages of MALDI imaging for de novo molecular features characterization and LMD-based microproteomics. [less ▲]

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See detailOsteopontin predicts radiotherapy response of glioblastoma patients : new role in DNA damage repair
Henry, Aurélie ULg; Nokin, Marie-Julie; Leroi, Natacha ULg 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 detailDiscovery of novel accessible proteins for therapeutic targeting of hepatocellular carcinoma.
Turtoi, Andrei ULg; Otaka, Y; Rokudai, S et al

in Acta Gastro-Enterologica Belgica (2016, March), 79(1), 13

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See detailAzacytidine and Decitabine prevent experimental sclerodermic chronic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

Poster (2016, January 29)

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following allo-transplantation, 60% of the patients experience ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following allo-transplantation, 60% of the patients experience chronic GVHD while approximately 15% of them develop a sclerodermic form of chronic GVHD characterized by multiple organ fibrosis and loss of skin elasticity. Regulatory T cells (Tregs) play a pivotal protective role in the pathogenesis of chronic GVHD by inhibiting alloreactive conventional T cells (Tconvs). Several studies have shown that hypomethylating agents such as Azacytidine (AZA) or Decitabine (DAC) can demethylate the master transcription factor of Treg (FoxP3), thus promoting Treg differentiation from Tconvs. This work investigates the impact of AZA and DAC in a murine model of sclerodermic chronic GVHD. Methods: Lethally irradiated (7 Gy) BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107splenocytes from B10.D2 donor mice to induce scl-cGVHD. Recipients were injected with 0.5 or 2 mg/kg of AZA or 0.75 mg/kg of DAC every 48h from day 10 to 30 following transplantation. GVHD was scored using a five criteria scale (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10. Results: Mice treated with AZA 0.5 mg/kg (n=14) or 2 mg/kg (n=17) or DAC 0.75 mg/kg (n=5) had lower clinical scores of GVHD compared to control (n=15). FACS analyses showed a higher proportion of Treg in the blood of AZA 0.5 or 2 mg/kg or DAC 0.75 mg/kg mice than in control at day 35. Results also showed a decreased number of Tconv and CD8 in AZA and DAC treated mice while proliferation of these cells expressing Ki67 was lower during AZA/DAC treatment but higher after discontinuation. Histological analyses showed less skin fibrosis in mice treated with 2 mg/kg of AZA. Finally, analyses of the blood components demonstrated that AZA mice were leuco- and lymphopenic as compared to control at day 21 and 35. Conclusion : AZA and DAC prevented sclerodermic GVHD in this murine model. [less ▲]

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See detailIn vitro monitoring of human tissue degradation by TD-GC×GC-TOFMS
Stefanuto, Pierre-Hugues ULg; Dubois, Lena ULg; DELPORTE, Géraldine ULg et al

Conference (2016, January 27)

Human rescue dog unit are amongst the most efficient tools to locate cadaver or individuals trapped after a natural disaster. However, the dog training process is long and expensive. Dog trainers are ... [more ▼]

Human rescue dog unit are amongst the most efficient tools to locate cadaver or individuals trapped after a natural disaster. However, the dog training process is long and expensive. Dog trainers are still looking for a better understanding of the dog olfaction matching mechanism to improve their training methods (1). How does the decomposition process differ between organs? Are there specific body parts better suited for dog training? What are the major volatile compounds responsible of the dogs’ match response? In the line of these questions, this project was monitoring the headspace of various human organs during the decomposition process. Five different organs, from five different bodies, were used: heart, lung, liver, kidney, and blood. Each organs were sampled in triplicates and let to decompose in glass jar. Regularly, the headspace of the jar was sampled by dynamic pumping to sorbent tubes that were further be desorbed on a comprehensive two-dimensional gas chromatography system (GC×GC). GC×GC is a powerful analytical tool that allows the resolution of “the smell of death”, i.e. the decomposition odor (2-3). The development of an in vitro approach for decomposition monitoring provided several analytical improvements in the decomposition field. Indeed, the study of dead bodies is always limited in the number of replicates (4). The sampling process developed for this project allows intra and inter corpse comparison with at least triplicates sampling. These comparisons were conducted using advanced chemometric methods (Fisher ratio, PCA, hierarchical analysis…) that will contribute to better understand key parameters of rescue the dog training. References 1. Hoffman et al. FSI (2009) 186, 6-13. 2. Stefanuto et al. CPC (2014) 79, 786-789. 3. Perrault et al. J. Sep. Sci. (2015) 38, 73-80. 4. Stefanuto et al. ABC (2015) 407, 4767-4778 [less ▲]

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See detailSeeking for Organ-specific VOC Signatures in Human Cadaveric Decomposition
Stefanuto, Pierre-Hugues ULg; Dubois, Lena ULg; Loyd, R et al

Conference (2016, January)

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

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

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See detailMyoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer
Fahmy, Karim ULg; Gonzalez, Arnaud ULg; Arafa, Mohammad et al

in International Journal of Cancer = Journal International du Cancer (2016), 138

Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas ... [more ▼]

Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC-3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin-silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC-3 myoferlin-silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density. [less ▲]

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