6 results on '"Yoann Daniel"'
Search Results
2. Data from Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemoresistance
- Author
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Anne Corlu, Florian Cabillic, Orlando Musso, Bernard Fromenty, Fabrice Morel, Claudine Rauch, Denise Glaise, Yoann Daniel, Romain Désert, Hélène Dubois-Pot-Schneider, and Karim Fekir
- Abstract
Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies. Gene expression profiling of HepaRG-SP and HepaRG-Spheres revealed enriched signatures related to cancer stem cells, metastasis, and recurrence and showed that HepaRG progenitors could retrodifferentiate into an immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells expressed high levels of cytokines triggering retrodifferentiation and displayed high migration and invasion potential. They also showed changes in mitochondrial activity with reduced membrane potential, low ATP production, and high lactate production. These changes were, in part, related to angiopoietin-like 4 (ANGPTL4)–induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Upregulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Therefore, restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCC.Significance:Restoring mitochondrial function in human hepatocellular carcinomas overcomes cancer resistance.
- Published
- 2023
3. Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction
- Author
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Florian Reizine, Murielle Grégoire, Mathieu Lesouhaitier, Valentin Coirier, Juliette Gauthier, Céline Delaloy, Elise Dessauge, Florent Creusat, Fabrice Uhel, Arnaud Gacouin, Frédéric Dessauge, Cécile Le Naoures, Caroline Moreau, Claude Bendavid, Yoann Daniel, Kilian Petitjean, Valérie Bordeau, Claire Lamaison, Caroline Piau, Vincent Cattoir, Mikael Roussel, Bernard Fromenty, Christian Michelet, Yves Le Tulzo, Jaroslaw Zmijewski, Ronan Thibault, Michel Cogné, Karin Tarte, Jean-Marc Tadié, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Etablissement Français du Sang Bretagne, EFS, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ARN régulateurs bactériens et médecine (BRM), Centre National de Référence de la Résistance aux Antibiotiques [CHU Rennes] (CNR), University of Alabama at Birmingham [ Birmingham] (UAB), This work was supported by funding from the Société de Réanimation de Langue Française (SRLF, Bourses Master 2 SRLF). We also thank the animal house Animalerie Rennaise Centre d’Hébergement et d’Expérimentation (ARCHE) platform and H2P2 platform (Structure Fédérative de Recherche [SFR] Biosit), and Aude Bodin for her help with mitochondrial functions analysis., Jonchère, Laurent, and Center of Experimental and Molecular Medicine
- Subjects
Immunosuppression Therapy ,Multidisciplinary ,Myeloid-Derived Suppressor Cells ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Biological Availability ,T cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Arginine ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Mitochondria ,Mice, Inbred C57BL ,[SDV] Life Sciences [q-bio] ,Disease Models, Animal ,Mice ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Sepsis ,Immune Tolerance ,Animals ,Cytokines ,Citrulline ,Female - Abstract
International audience; Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.
- Published
- 2022
4. Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells
- Author
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Caroline Aninat, Yoann Daniel, Anne Corlu, Elise Lelou, Florian Cabillic, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
- Subjects
0301 basic medicine ,Cancer Research ,cancer stem cell ,[SDV]Life Sciences [q-bio] ,Review ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Cell Plasticity ,Epithelial–mesenchymal transition ,Transcription factor ,RC254-282 ,Glutaminolysis ,cell plasticity ,metabolism reprogramming ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Cell biology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,epithelial-to-mesenchymal transition ,Stem cell ,Reprogramming ,catecholamines - Abstract
Simple Summary Tumor cells display important plasticity potential. Notably, tumor cells have the ability to change toward immature cells called cancer stem cells under the influence of the tumor environment. Importantly, cancer stem cells are a small subset of relatively quiescent cells that, unlike rapidly dividing differentiated tumor cells, escape standard chemotherapies, causing relapse or recurrence of cancer. Interestingly, these cells adopt a specific metabolism. Most often, they mainly rely on glucose uptake and metabolism to sustain their energy needs. This metabolic reprogramming is set off by environmental factors such as pro-inflammatory signals or catecholamine hormones (epinephrine, norepinephrine). A better understanding of this process could provide opportunities to kill cancer stem cells. Indeed, it would become possible to develop drugs that act specifically on metabolic pathways used by these cells. These new drugs could be used to strengthen the effects of current chemotherapies and overcome cancers with poor prognoses. Abstract Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.
- Published
- 2021
5. Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity
- Author
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Julien Allard, Simon Bucher, Julie Massart, Pierre-Jean Ferron, Dounia Le Guillou, Roxane Loyant, Yoann Daniel, Youenn Launay, Nelly Buron, Karima Begriche, Annie Borgne-Sanchez, Bernard Fromenty
- Published
- 2020
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6. Retrodifferentiation of human tumor hepatocytes to stem cells leads to metabolic reprogramming and chemoresistance
- Author
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Orlando Musso, Anne Corlu, Bernard Fromenty, Karim Fekir, Florian Cabillic, Hélène Dubois-Pot-Schneider, Fabrice Morel, Romain Desert, Yoann Daniel, Claudine Rauch, Denise Glaise, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle Grand Ouest, Association pour la Recherche sur le CancerAssociation pour la Recherche sur le Cancer (ARC), University of Rennes, Ligue Contre le CancerLigue Contre le Cancer, Conseil Régional de BretagneConseil Régional de Bretagne (Brittany Council), Institut National de la Santé et de la Recherche MédicaleInstitut National de la Santé et de la Recherche Médicale (Inserm), 223317, Seventh Framework ProgrammeSeventh Framework Programme (FP7), 12688, Institut National Du CancerInstitut National Du Cancer (INCa), Centre National de la Recherche ScientifiqueCentre National de la Recherche Scientifique (CNRS), Contrat plan etat region, and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,Cancer Research ,Carcinoma, Hepatocellular ,transdifferentiation ,Cellular differentiation ,[SDV]Life Sciences [q-bio] ,Apoptosis ,Biology ,growth-factor ,advanced hepatocellular-carcinoma ,Transcriptome ,resistance ,03 medical and health sciences ,0302 clinical medicine ,Side population ,Cancer stem cell ,liver-cancer ,expression ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,metastasis ,Progenitor cell ,Cell Proliferation ,angiopoietin-like 4 ,Liver Neoplasms ,Cell Differentiation ,Cellular Reprogramming ,Prognosis ,digestive system diseases ,3. Good health ,Survival Rate ,030104 developmental biology ,Oncology ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Hepatocytes ,Neoplastic Stem Cells ,sorafenib ,regorafenib ,Stem cell ,Neoplasm Recurrence, Local - Abstract
Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies. Gene expression profiling of HepaRG-SP and HepaRG-Spheres revealed enriched signatures related to cancer stem cells, metastasis, and recurrence and showed that HepaRG progenitors could retrodifferentiate into an immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells expressed high levels of cytokines triggering retrodifferentiation and displayed high migration and invasion potential. They also showed changes in mitochondrial activity with reduced membrane potential, low ATP production, and high lactate production. These changes were, in part, related to angiopoietin-like 4 (ANGPTL4)–induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Upregulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Therefore, restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCC. Significance: Restoring mitochondrial function in human hepatocellular carcinomas overcomes cancer resistance.
- Published
- 2019
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