Marie-Odile Jauberteau

Centre Hospitalier Universitaire de Limoges, Limages, Limousin, France

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Publications (37)109.05 Total impact

  • Current Drug Metabolism 09/2014; · 4.41 Impact Factor
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    ABSTRACT: The transfer of exosomes containing both genetic and protein materials is necessary for the control of cancer cell microenvironment to promote tumor angiogenesis. The nature and function of proteins found in the exosomal cargo, their mechanisms in membrane transport and related signaling events are not clearly understood. In this study, we demonstrate in human lung cancer A549 cells, that the exosome release mechanism is closely linked to a multifaceted receptor, neurotensin (NT) receptor-3 also called sortilin. Sortilin is already known to be important for cancer cell function. Here, we report for the first time its role in the assembly of a tyrosine kinase complex and subsequent exosome release. This novel complex (TES complex) found in exosomes results in the linkage of two tyrosine kinase receptors, TrkB and EGFR with sortilin. Using in vitro models, we demonstrate that this complex containing sortilin exhibits a control on endothelial cells and angiogenesis activation through exosome transfer.
    Journal of Cell Science 07/2014; · 5.88 Impact Factor
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    ABSTRACT: The development of methods to enrich cell populations for cancer stem cells (CSC) is urgently needed to help understand tumor progression, therapeutic escape and to evaluate new drugs, in particular for colorectal cancer (CRC). In this work, we describe the in vitro use of OncoMiD for colon, a CRC-specific primary cell culture medium, to enrich CRC cell lines in CSC. Sedimentation field flow fractionation (SdFFF) was used to monitor the evolution of subpopulations composition. In these models, medium induced a loss of adherence properties associated with a balance between proliferation and apoptosis rates and, more important, an increased expression of relevant CSC markers, leading to specific SdFFF elution profile changes.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 05/2014; 963C:40-46. · 2.78 Impact Factor
  • CNS & neurological disorders drug targets 05/2014; · 3.57 Impact Factor
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    ABSTRACT: Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells. Two major hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential. These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer (CRC), one of the most commonly diagnosed and lethal cancers worldwide. The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. Furthermore, the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells. These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy, such as with bevacizumab, a monoclonal antibody against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients. However, such treatments are not completely curative, and a large proportion of patient tumors retain chemoresistance or show recurrence. This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells, as well as discusses the mechanisms contributing to their maintenance. Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks, namely angiogenic and proliferative attributes, could improve survival and decrease adverse effects induced by unnecessary chemotherapy.
    World Journal of Gastroenterology 04/2014; 20(15):4189-4196. · 2.55 Impact Factor
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    ABSTRACT: The development of methods to enrich cell populations for cancer stem cells (CSC) is urgently needed to help understand tumor progression, therapeutic escape and to evaluate new drugs, in particular for colorectal cancer (CRC). In this work, we describe the in vitro use of OncoMiD for colon, a CRC-specific primary cell culture medium, to enrich CRC cell lines in CSC. Sedimentation field flow fractionation (SdFFF) was used to monitor the evolution of subpopulations composition. In these models, medium induced a loss of adherence properties associated with a balance between proliferation and apoptosis rates and, more important, an increased expression of relevant CSC markers, leading to specific SdFFF elution profile changes.
    Journal of Chromatography B. 01/2014; 963:40–46.
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    ABSTRACT: SdFFF is now commonly used for cell sorting. Nevertheless, as with many other separation methods, SdFFF Hyperlayer elution leads (1) to sample dilution resulting in cell loss which could restrict further use; and (2) to a high output flow rate impacting detector sensitivity and selectivity. In order to limit these problems, we proposed modifications of the SdFFF separation channel consisting both in downscaling and the insertion of an outlet stream splitter. This last system corresponded to a strip which divides the flow rate output into two parts, one containing concentrated cells in a reduced volume and flow rate, the other containing the excess mobile phase useless for further cell manipulation, detection and characterization. For the first time we have shown that splitter implementation and downscaling respected channel flowing and resulted in Hyperlayer elution of around 95% of cells in less than 50% of input flow rate. Improved cell sorting was demonstrated by enrichment (∼10 times) of cancer stem cells from WiDr cells with two times less quantity of injected cells.
    Journal of Chromatography A 06/2013; · 4.61 Impact Factor
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    ABSTRACT: Solid tumors like neuroblastoma exhibit hypoxic areas, which can lead both to cell death or aggressiveness increase. Hypoxia is a known stress able to induce stabilization of p53, implicated in cell fate regulation. Recently, p53 appeared to be involved in autophagy in an opposite manner, depending on its location: when nuclear, it enhanced transcription of pro-autophagic gene whereas when cytoplasmic, it inhibited the autophagic process. Today, we used cobalt chloride, a hypoxia mimetic that inhibits proteasomal HIF-1 degradation and generates reactive oxygen species (ROS). We focused on CoCl(2)-induced cell death in a DNA-binding mutated p53 neuroblastoma cell line (SKNBE(2c). An autophagic signalling was evidenced by an increase of Beclin-1, ATG 5-12, and LC3-II expression whereas the p53(mut) presence decreased with CoCl(2) time exposure. Activation of the pathway seemed to protect cells from ROS production and, at least in part, from death. The autophagic inhibitors activated the apoptotic signalling and the death was enhanced. To delineate the eventual implication of the p53(mut) in the autophagic process in response to hypoxia, we monitored signalling in p53(WT)SHSY5Y cells, after either shRNA-p53 down-regulation or transcriptional activity inhibition by pifithrin alphaWe did not detect autophagy neither with p53(wt) nor when p53 was lacking whereas such a response was effective with a mutated or inactivated p53. To conclude, mutated p53 in neuroblastoma cells could be linked with the switch between apoptotic response and cell death by autophagy in response to hypoxic mimetic stress.
    Biochemical pharmacology 02/2013; · 4.25 Impact Factor
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    ABSTRACT: Microglial cells constitute the first line of defense of the central nervous system (CNS) against microbial invasion. Pathogens are detected thanks to an array of innate immune receptors termed pattern recognition receptors (PRRs). PRRs have been thoroughly characterized in bone marrow-derived macrophages, but the PRRs repertoire and functionality in microglial cells remain largely unknown. Microglial cells express various Toll-like Receptors and the Nod1/2 receptors. Recently, a novel innate immune signalling pathway, the inflammasome pathway has been uncovered. Inflammasome activation leads to caspase-1 activation, release of the proinflammatory cytokines, IL-1β and IL-18 and cell death in a process termed pyroptosis. One inflammasome receptor, NLRP3, has been characterized in microglial cells and associated with response to infections and in the initiation of neuro-degeneration in an Alzheimer's disease model. Legionella pneumophila (L.pneumophila) is a flagellated bacterium replicating within macrophages. In bone marrow-derived macrophages, L. pneumophila is detected in a flagellin-dependent manner by the Naip5-NLRC4 (Ipaf) inflammasome pathway. In this study, we decided to use L. pneumophila to investigate the presence and the functionality of this inflammasome in primary murine microglial cells. We show that microglial cells detect L. pneumophila infection in a flagellin-dependent manner leading to caspase-1-mediated bacterial growth restriction, infected cell death and secretion of the proinflammatory cytokines IL-1β and IL18. Overall, our data demonstrate that microglial cells have a functional Naip5-NLRC4 inflammasome likely to be important to monitor and clear CNS infections by flagellated bacteria. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.
    Glia 01/2013; · 5.07 Impact Factor
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    ABSTRACT: Neurotrophins play a central role in the development and maintenance of the nervous system. However, neurotrophins can also modulate B and T cell proliferation and activation, especially via autocrine loops. We hypothesized that both serum and lymphocytic neurotrophin levels may be deregulated in systemic Lupus erythematosus (SLE) and may reflect clinical symptoms of the disease. Neurotrophins in the serum (ELISA tests) and lymphocytes (flow cytometry) were measured in 26 SLE patients and 26 control subjects. Th1 (interferon-γ) and Th2 (IL-10) profiles and serum concentration of BAFF were assessed by ELISA in the SLE and control subjects. We have demonstrated that both NGF and BDNF serum levels are higher in SLE patients than healthy controls (p=0.003 and p<0.001), independently of Th1 or Th2 profiles. Enhanced serum NT-3 levels (p=0.003) were only found in severe lupus flares (i.e. SLEDAI ≥ 10) and significantly correlated with complement activation (decreased CH 50, Γ=-0.28, p=0.03). Furthermore, there was a negative correlation between serum NGF levels and the number of circulating T regulatory cells (Γ=0.48, p=0.01). In circulating B cells, production of both NGF and BDNF was greater in SLE patients than in healthy controls. In particular, the number of NGF-secreting B cells correlated with decreased complement levels (p=0.05). One month after SLE flare treatment, BDNF levels decreased; in contrast, NGF and NT-3 levels remained unchanged. This study demonstrates that serum and B cell levels of both NGF and BDNF are increased in SLE, suggesting that the neurotrophin production pathway is deregulated in this disease. These results must be confirmed in a larger study with naive SLE patients, in order to avoid the potential confounding influence of prior immune-modulating treatments on neurotrophin levels.
    PLoS ONE 01/2013; 8(11):e79414. · 3.53 Impact Factor
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    ABSTRACT: Photodynamic therapy (PDT) is now a well-established treatment modality for cutaneous carcinomas and is based on the administration of a light-activated drug followed by illumination of the pathological area. The treatment of metastatic melanoma remains a therapeutic challenge. To define the possible role of melanin in relative phototoxicity of 5-aminolevulinic acid (5-ALA), a photosensitizer used in PDT in vivo, we studied cell death in two variants (with or without melanin, B16F10 and B16G4F cells, respectively) of a melanoma cell line. Concentrations of 5-Ala up to 10 mM induced similar cytostatic effects in the B16G4F and B16F10 cells. PDT and high 5-ALA concentrations induced photocytotoxicity in both melanoma cell lines (at 10 mM for B16F10 cells and at 5 mM for B16G4F cells). Cell death corresponded to p53-dependent apoptotic signaling in pigmented B16F10 cells, whereas an autophagic response leading to a caspase-independent death was detected in non-pigmented B16G4F cells. Therefore, the PDT-induced cell death pathway appeared to correlate with melanin synthesis capacity in melanoma cells. To reduce the cytotoxicity of 5-ALA without irradiation, a low drug concentration could be used. Consequently, in combination with current therapeutics, a moderate concentration of 5-ALA and PDT may constitute a supplementary promising approach to eliminate metastatic melanoma.
    Oncology Reports 12/2012; · 2.30 Impact Factor
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    ABSTRACT: Neurotensin, a neuropeptide growth factor, and its two specific neurotensin receptors, NTSR1 and NTSR2, were shown to be expressed by human B cell lines. Another NTSR, sortilin, which is common to neurotensin and neurotrophins, was also detected as we have previously described. Neurotensin was functional in B cell lines; it induced their proliferation and inhibited apoptosis induced by serum deprivation or Fas activation. Quantitative study of gene expression in two malignant B cell diseases showed that NTSR2 was overexpressed, NTSR1 decreased, and neurotensin was unexpressed in B cell leukemia patient's cells, as compared with healthy B cells. However, these expressions did not significantly change in large diffuse B cell lymphoma lymph nodes compared with benign ones. This study points out that neurotensin and its two specific receptors are expressed in human B lymphocytes. Such expressions were not described, and their relationship in B cell diseases, especially in chronic B cell leukemia, needs to be considered further in regard to these findings.
    The Journal of Immunology 10/2012; · 5.52 Impact Factor
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    ABSTRACT: The development of hypoxic areas often takes place in solid tumors and leads cells to undergo adaptive signalization like autophagy. This process is responsible for misfolded or aggregated proteins and nonfunctional organelle recycling, allowing cells to maintain their energetic status. However, it could constitute a double-edged pathway leading to both survival and cell death. So, in response to stress such as hypoxia, autophagic and apoptotic cells are often mixed. To specifically study and characterize autophagic cells and the process, we needed to develop a method able to (1) isolate autophagic subpopulation and (2) respect apoptotic and autophagic status. Sedimentation field-flow fractionation (SdFFF) was first used to monitor physical parameter changes due to the hypoxia mimetic CoCl2 in the p53 mutated SKNBE2(c) human neuroblastoma cell line. Second, we showed that “hyperlayer” elution is able to prepare autophagic enriched populations, fraction (F3), overexpressing autophagic markers (i.e., LC3-II accumulation and punctiform organization of autophagosomes as well as cathepsin B overactivity). Conversely, the first eluted fraction exhibited apoptotic markers (caspase-3 activity and Bax increased expression). For the first time, SdFFF was employed as an analytical tool in order to discriminate apoptotic and autophagic cells, thus providing an enriched autophagic fraction consecutively to a hypoxic stress.
    Analytical Chemistry. 10/2012; 84(20):8748–8755.
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    ABSTRACT: A high incidence of colorectal cancer (CRC) has been established in the elderly population. Apoptosis is a key event in maintaining colon homeostasis, both in aging as well as in cancer prevention. Here, we report that colon morphology is affected during the aging process: crypt loss (P=0.045) and increasing distances between crypts (P=0.0001678) were observed, associated with a tendency for mucosa reduction (P=0.083). In addition, our results show that apoptosis plays a determining role on the effect of aging during CRC. Increased expression of cleaved caspase 3 (the key factor implicated in the caspase-dependent pathway; P=0.026 for non-tumor tissues, P=0.0013 for tumor tissues) and AIF (implicated in the caspase-independent pathway; P=0.037) in tissue from elderly patients has been observed. Furthermore, elderly patients respond better to chemotherapy than younger ones (P=9.27 x 10(-5)). These results suggest that patient age should be taken into account to adapt treatment of CRC.
    Oncology Reports 03/2012; 27(6):1787-93. · 2.30 Impact Factor
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    ABSTRACT: Recently, cancer stem cells (CSCs) have been identified in many types of cancers, such as colorectal cancer (CRC). CSCs seem to be involved in initiation, growth, and tumor metastasis, as well as in radio- and chemotherapy failures. CSCs appears as new biological targets for cancer therapy, requiring the development of noninvasive cell sorting methods. In this study, we used sedimentation field flow fractionation (SdFFF) to prepare enriched populations of CSCs from eight cell lines corresponding to different CRC grades. On the basis of phenotypic and functional characterizations, "hyperlayer" elution resulted in a fraction overexpressing CSC markers (CD44, CD166, EpCAM) for all cell lines. CSCs were eluted in the last fraction for seven out of eight cell lines, but in the first for HCT116. These results suggest, according to the literature, that two different pools of CSCs exist, quiescent and activated, which can both be sorted by SdFFF. Moreover, according to CSC properties, enriched fractions are able to form colonies.
    Analytical Chemistry 02/2012; 84(3):1549-56. · 5.70 Impact Factor
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    ABSTRACT: This paper illustrates the potential of microwave frequencies for biological analysis. Once penetrating inside biological cells, microwaves can interact with their intracellular content and inform on their safe or malignant state. This work demonstrates that their cancer grade (i.e. aggressiveness level) can also be identified by this way. Hence, based on permittivity measurements on three colon cancer cell lines loading RF resonators, the presented results show significant differences of electromagnetic signature in the cancer grade of analyzed cells. This sensing method appears very promising to develop new powerful tools for early cancer diagnostic.
    Microwave Symposium Digest (MTT), 2012 IEEE MTT-S International; 01/2012
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    ABSTRACT: Glioblastoma Multiforme (GBM) is the most frequent malignant brain tumor with still poor prognosis. Tumor initiation, growth and recurrences might depend on Brain Tumor Stem Cells (BTSCs) which can promote tumor aggressiveness and potentially affords new therapeutic target. Recent works emphasized aberrant cell-surface glyco-conjugate expression in brain tumors suggesting that altered glycosylation is closely linked to cancer tumor metastasis and invasive process. Post-translational changes might play a key role in determining the fates of most aggressive and undifferentiated cells such as self-renewal, proliferation and differentiation. In order to characterize the glycosylation-related genes involved in differentiation status of the BTSCs, two glioblastoma cell lines, U87-MG and U251 have been cultured according to two conditions leading to undifferentiated floating cells or differentiated adherent cells. The expression level of 559 glycosylation related genes has been analyzed by Taqman Low Density Array (TLDA) analysis and allowed to isolate eight up-regulated genes specific of a subpopulation of undifferentiated cells. Protein expression has been confirmed. Among main selected genes, five are also over-expressed in the undifferentiated condition in primary cultures provided by three GBM freshly isolated from patient. This work suggests that new Glycosylation-related gene signature might improve the characterization of the most aggressive and undifferentiated cells and supports that in future, N-linked glycosylation might provide new target to develop therapeutic strategy for inhibiting tumor growth.
    Cancer letters 08/2011; 312(1):24-32. · 4.86 Impact Factor
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    ABSTRACT: Apoptosis has to be drastically controlled in organs with important cell turnover such as the colon. Deregulation of this process is often present in tumor progression. Tissues of 82 patients treated for colorectal cancer (CRC) were analyzed using antibodies against AIF, p53, DR4, DR5, cleaved caspase-3 and the TUNEL method to detect apoptosis; whereas staining of Ki-67 was used as a proliferation marker. In situ immunohistochemical analyses were compared in non-tumor (NT) cells from normal adjacent mucous membranes with tumor (T) cells from patients with Stage I (n=6), Stage II (n=35), Stage III (n=27) and Stage IV (n=14) CRC. Results were correlated with the tumor stages and the treatment response of patients to improve the understanding of CRC development. p53 and DR5 expression decreased progressively with CRC stage, suggesting that these proteins are important markers of advanced tumor stages. Moreover, p53 appears as a prognostic factor to predict recurrence-free survival. Including the detection of p53 and DR5 for establishing the diagnosis of CRC and adapting the treatment to each patient is strongly suggested by our work.
    Oncology Reports 07/2011; 26(5):1091-7. · 2.30 Impact Factor
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    ABSTRACT: The Fas pathway is described as an activator of the glioblastoma proliferation by increasing the pathogenicity of this tumour. The lipopolysaccharide (LPS) pathway depending on Toll-like receptor 4 (TLR4) could limit the glioblastoma spreading. Here, Fas and TLR4 pathways were activated in glioblastoma cell lines by an agonist antibody and/or LPS treatment. Activation of the Fas pathway or of the TLR4 pathway induced cell proliferation. However, simultaneous treatment with agonist antibody and LPS decreased proliferation. This anti-proliferative effect was caspase dependent, and a decreased cell migration and matrix metalloproteinase (MMP)-9 expression were also observed. Both TLR4 and MMP-9 were highly expressed in human glioblastoma tissues. These data suggest that TLR4 signal transduction pathways neutralize proliferation and migration induced by Fas pathway activation in glioblastoma cell lines.
    Cancer letters 07/2011; 311(2):195-202. · 4.86 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL. In the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75(NTR)/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab. Collectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.
    PLoS ONE 01/2011; 6(11):e27213. · 3.53 Impact Factor

Publication Stats

220 Citations
109.05 Total Impact Points

Institutions

  • 2013
    • Centre Hospitalier Universitaire de Limoges
      • Department of Neurology
      Limages, Limousin, France
  • 2008–2012
    • University of Limoges
      • Faculté de Pharmacie
      Limages, Limousin, France
  • 2003
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France