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Teses / dissertações sobre o assunto "Exosomes – Dissertation universitaire":
Perbet, Romain. "Rôle des vésicules extracellulaires dans la propagation de la protéine Tau". Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S023.
Intra-neuronal accumulation of tau protein aggregates is one of the common feature of a group of heterogeneous neurodegenerative diseases called tauopathies. In some of them, the pathology will first affect a region before spreading to other regions.This staging could be linked to the prion-like propagation of pathological seed-competent tau species. These seeds, identified in transgenic mice interstitial fluid (ISF) and in human cerebrospinal fluid (CSF) are uptaken by cells and induce subsequent intracellular tau aggregation (Takeda et al., 2016). The pathological species of tau which are spreading are not yet well characterized but several mechanisms mediating their transfer (secretion and capture) have been highlighted. Among them, we demonstrated that tau is secreted in extracellular vesicles (EV´s) (Dujardin et al., 2014). We also know that neurons are implicated in this transfer but the role of glial cells is unknown.In this context, we wanted to: 1 / demonstrate that pathological Tau protein is present in EVs extracted from brain of patients suffering from different Tauopathy and that those EVS induce pathology in animals. 2 / detect pathological Tau species in EVs extracted from plasma and CSF, potential biomarkers of Tauopathies. 3 / demonstrate that Tau protein can be transferred from neuron to astrocyte and, if so, to determine the transfer pathway.To test the seeding potential of EV’s containing in ISF derived from human brain of patient presenting tauopathies, and Tau 30 mouse brain we have used a sensitive and specific tau biosensor assay. Our results demonstrate that EVs isolated from ISF of AD patient, PSP patient and Tau 30 mouse contain seed prion-like properties. The ability of these seeds to recruit tau seems to be correlated to the severity of tau pathology (prefrontal>occipital>cerebellum) for AD. This might reflect the slight presence of neurofibrillary degeneration as well as extracellular tau in this pathology in comparison to AD. Finally, the presence of seeds-containing EV’s in the extracellular space supports the idea that these shuttles might be implied in the prion-like propagation of tau pathology in Humans. Additionally, tau pathology spreading is driven by EV’s rather than by free-floating tau species.We also demonstrated that tau can be transferred from neuron to astrocyte; this transfer is more efficient with EV’s than with free floating tau.These data open new avenues for therapeutic interventions that might targets the toxic and propagative species
Quilbe, Alexandre. "Évaluation in vitro et in vivo de deux nouvelles stratégies thérapeutiques ciblées dans l'adénocarcinome pancréatique : une immunothérapie ciblant l’Immune Checkpoint Galectine-9 et une thérapie photodynamique ciblant le récepteur folate". Thesis, Lille, 2020. https://pepite-depot.univ-lille.fr/RESTREINT/EDBSL/2020/2020LILUS034.pdf.
Recently, other and our team have demonstrated that a high regulatory T lymphocytes (Treg) prevalence promotes tumor progression by inhibiting anti-tumor immune response. This was further substantiated by other studies on various cancer models. Using this knowledge, our laboratory has developed a new immunotherapy strategy targeting immunosuppressive activity of human natural Treg (CD4+ CD25high FoxP3+ CD127-/Low). This strategy targets Galectin-9 (Gal-9) produced and secreted by Treg cells using an anti Gal-9 monoclonal antibody (Patent WO2015185875). Thus, for the first time, we demonstrated that an anti-Gal-9 immunotherapy can significantly limit tumor growth in a humanized mouse model of nasopharyngeal carcinoma. In parallel, it have been shown a high Gal-9 expression in a mouse model of pancreatic cancer (PDAC), and a high prevalence of circulating and infiltrating Treg in PDAC patients. Thus, PDAC appears to be a privileged target for our anti-Gal-9 immunotherapy. In this context, our main objective was to evaluate the in vitro and in vivo efficacy of our anti-Gal-9 immunotherapy in PDAC. In close collaboration, with Dr. Isabelle Vanseuningen (JPARC, Lille), we were first able to evaluate the expression of Gal-9 and the prevalence of Treg from the earliest stages of pancreatic carcinogenesis in a transgenic mouse model. We have also evaluated the efficiency of anti-Gal9 treatment on tumor pancreatic progression. Our data demonstrated that the neutralization of Gal-9 was successful in limiting Treg infiltration along with neoplastic lesion progression. In a second time, in order to anticipate the use of this immunotherapy in humans, we also validated Gal-9 expression (RT-qPCR, Immunofluorescence, Western blot and cytometry) in 4 different human pancreatic cancer lines (Capan-1, Capan-2, MIAPaCa-2, PANC-1). Interestingly, we showed that these lines secrets Gal-9 in particular via exosomes (ELISA, Western-Blot). Finally, in vivo results suggested that our anti-Gal-9 antibody limits not only exosomes immunosuppressive impact, but also the tumor growth in a humanized mouse model of PDAC.Furthermore, we have initiated a novel study to evaluate a new therapeutic strategy for PDAC: The Photodynamic Therapy (PDT). PDT is based on the use of a non-toxic photosensitizer (PS) and a light excitation. Upon accumulation in the neoplasm and subsequent photo-excitation, the PS generates reactive oxygen species to elicit tumoral cytotoxicity. In the recent years, PDT has already proved its worth in the field of oncology. There is indeed a rationale to think that PDT could impact the immune response, in favor of immunoactivation against the tumor. In the laboratory, we have a new folate-coupled PS (PS2), protected by a recently published patent (WO2019 016397-A1, January 24, 2019), which binds with folate receptor 1 (FOLR1). FOLR1 is expressed in 100% of ADKPs, and even over-expressed in 30%. In this context, the objective was to evaluate the efficacy of PDT on 4 human PDAC lines: Capan-1, Capan-2, MiaPaca-2 and Panc-1. We validated the genomic and proteomic expression of FOLR1 on the 4 PDAC cell lines. Subsequently, we confirmed the efficacy of PS2 mediated PDT our 4 tumor cell lines. Our results also demonstrated that PDT affects the cytokine secretion of cancer cell lines and the conditioned media of these PS2-PDT-treated cells had a proliferative effect on the human immune system. Finally, we showed that PS2-PDT limits the tumor growth of our immunocompromised humanized mice (SCID) model with subcutaneously transplanted MIAPaCa-2 cells.In conclusion, our investigations suggest not only that PS2-PDT is an effective targeted therapy in the treatment of ADKP but also that it activates the immune system and plays the role of a real adjuvant anti-cancer vaccination
Manier, Salomon. "Ciblage de MYC par étude de l'axe LIN28B/let-7 et de l'initiation de la traduction dans le myélome multiple". Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S012/document.
MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells suggested that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM. We next sought to establish new biomarkers in MM, enable to capture the molecular alterations of the disease. For this purpose, we examined the prognostic significance of circulating exosomal microRNAs (miRNAs) in a cohort of 156 patients with newly diagnosed MM, uniformly treated and followed. Circulating exosomal miRNAs were isolated and used to perform small RNA sequencing analysis on 10 samples and a qRT-PCR array on 156 samples. We studied the relationship between miRNA levels and patient outcomes including progression-free survival (PFS) and overall survival (OS). We identified miRNAs as the most predominant small RNAs present in exosomes isolated from the serum of MM patients and healthy controls by small RNA sequencing of circulating exosomes and used a qRT-PCR assay to measure the expression of 22 exosomal miRNAs. Two of them, namely let-7b and miR-18a, were significantly associated with both PFS and OS in the univariate analysis, and were still statistically significant after adjusting for the International Staging System (ISS), and adverse cytogenetics in the multivariate analysis. Our findings support the use of circulating exosomal let-7b and miR-18a improves the identification of patients with newly diagnosed MM with poor outcomes. Finally, to better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small molecule library for anti-MM activity in cell lines with high expression of MYC. The most potent hits identified were rocaglate-scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide, reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in several mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates
Sikorska, Natalia. "The phosphorolytic activity of the exosome core complex contributes to rRNA maturation in Arabidopsis thaliana". Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ070/document.
The eukaryotic RNA exosome complex is the main 3’-5’ degradation machinery that plays an essential role in RNA decay, quality control and maturation. The exosome core complex (EXO9) is catalytically inert in yeast and humans, and therefore relies on the catalytic activity of associated RNases, Rrp6 and Rrp44. In this study I demonstrated that EXO9 is catalytically active in Arabidopsis. EXO9’s activity is phosphate-dependent, releases nucleoside diphosphates and is reversible, meeting all criteria of a phosphorolytic activity. Importantly, EXO9’s in vivo substrates include the archetypical exosome substrates, rRNA maturation by-products and 5.8S rRNA precursors. My data show that AtRRP44, EXO9 and AtRRP6L2 sequentially cooperate for the processing of 5.8S rRNA. This work sets a basis for studies aiming at further understanding the biological functions of EXO9’s phosphorolytic activity in a eukaryotic organism
Fleury, Audrey. "Caractérisation et fonction des vésicules extracellulaires sur le métabolisme adipocytaire : rôle du morphogène Sonic Hedgehog". Thesis, Angers, 2015. http://www.theses.fr/2015ANGE0079/document.
Extracellular vesicles (EV), including microparticles (MP) and exosomes, are able to modulate target cell function through exchange or transfer of biological material. Although EV are present in the blood of healthy individuals, an elevated quantity of circulating EV is associated with cardiovascular diseases, which obesity is a major cardiovascular risk factor. Nevertheless, few studies have reported the ability of adipocytes to release EV and their implication in adipose tissue metabolism. First of all, we could determine morphological and biochemical features of adipocyte-derived exosomes and MP through a combination of methods. We were able to demonstrate an increase in adipocyte EV production in a murine model of obesity. Proteomic analysis of adipocyte EV further revealed a specific enrichment of proteins crucial for glucose and lipid metabolism and related to inflammation in MP and exosomes respectively. We then evaluated the ability of lymphocytes-derived MP harboring the Sonic Hedgehog morphogen to control adipocyte differentiation. Activation of the Hedgehog canonical pathway inhibited adipogenesis, as did MPHh+. Surprisingly, although Smo dependent, inhibitory potential of such MP did not involve the Gli transcription factors. We show that MPHh+ inhibit adipocyte differentiation through a Smo/Lkb1/Ampk axis as does a new agonist of Smo, GSA-10. Our results demonstrate, on one hand, the ability of adipocyte to release EV and on the other hand, the capacity of MPHh+ to control adipogenesis through a non-canonical Hh signaling pathway. In conclusion, EV might contribute to obesity related metabolic dysfunctions through systemic regulation of metabolic pathways
Baloche, Valentin. "Contributions négatives et positives de la galectine-9 au développement tumoral : étude dans des modèles tumoraux murins syngéniques In the MB49 Murine Model, Genetic Ablation of Galectin-9 Enhances Anti-Tumor Immune Response: Possible Role of a Greater CXCL9/Il-6 Production Tumor Exosomal Micrornas Thwarting Anti-Tumor Immune Responses in Nasopharyngeal Carcinomas Interferon β and Anti-PD1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells Interferon Beta Increases NK Cell Cytotoxicity against Tumor Cells in Patients with Nasopharyngeal Carcinoma via Tumor Necrosis Factor Apoptosis-Inducing Ligand Emerging Therapeutic Targets for Nasopharyngeal Carcinoma: Opportunities and Challenges Galectin-9 Promotes a Suppressive Microenvironment in Human Cancer by Enhancing STING Degradation". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS117.
Like other galectins, galectin-9 (gal-9) is an animal lectin which interacts with a defined subgroup of glycans carried by glycoproteins or glycolipids. Gal-9 associated with cells performs multiple functions in the cytoplasm, in the nucleus and at the surface of the plasma membrane. Some publications suggest that intracellular gal-9 inhibits the mobility of malignant cells and exerts an anti-metastatic effect. In addition, gal-9 can be secreted into the extracellular medium where it behaves like a cytokine with mainly immunosuppressive effects. These effects have been demonstrated in the context of human tumors and in mouse tumor models. However, so far there was no murine tumor model available to assess the pro-tumor or anti-tumor effet of gal-9 independently of gal-9 produced by infiltrating cells. To address this issue, we derived isogenic clones invalidated or not for gal-9 from 2 murine tumoral lines : CT26 (BABL/c genetic background) and MB49 (C57BL/6 genetic background), using CRISPR/Cas9 technology. In the case of the MB49 line, we were able to demonstrate a remarkable phenotype in vivo. During serial transplantations, we saw, for tumors derived from invalidated clones, a dramatic reduction in tumor growth after 3 or 4 passages in syngenic mice but not in immunodeficient mice. The emergence of the immune response responsible for this arrest of tumor growth was investigated by immunohistochemistry, multiplex cytokine assay in tumor extracts and transcriptome analysis by RNAseq. Increased intra-tumor production of interferon-γ, CXCL9 and Il-6 appears to play an important role in enhancing the immune response against KO-gal-9 tumors