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7 results on '"Niclas Setterblad"'

1. Self-organization and culture of Mesenchymal Stem Cell spheroids in acoustic levitation

Author

Mauricio Hoyos, Jean-Luc Aider, Jérôme Larghero, Niclas Setterblad, Nathan Jeger-Madiot, Lousineh Arakelian, Patrick Bruneval, Physique et mécanique des milieux hétérogenes (UMR 7636) (PMMH), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service Commun d'Imagerie Cellulaire et Moléculaire, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Département de Pathologie [AP-HP Hôpital Européen Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Gestionnaire, Hal Sorbonne Université, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Stromal cell, Materials science, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Science, [SDV]Life Sciences [q-bio], Cell, 02 engineering and technology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Acoustic levitation, Article, Stem-cell biotechnology, Biomaterials, 03 medical and health sciences, 3D cell culture, Tissue engineering, medicine, Scaffold-free 3D culture, [PHYS.MECA.MEFL]Physics [physics]/Mechanics [physics]/Fluid mechanics [physics.class-ph], 030304 developmental biology, 0303 health sciences, Multidisciplinary, Cluster of differentiation, Mesenchymal Stromal Cells, Mesenchymal stem cell, Cell culture in acoustic levitation, Spheroid, Acoustics, 021001 nanoscience & nanotechnology, [PHYS.MECA.ACOU]Physics [physics]/Mechanics [physics]/Acoustics [physics.class-ph], [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Cell culture, Multi-trap acoustofluidic device, embryonic structures, Medicine, Spheroids, 0210 nano-technology, Biomedical engineering
Abstract

International audience; In recent years, 3D cell culture models such as spheroid or organoid technologies have known important developments. Many studies have shown that 3D cultures exhibit better biomimetic properties compared to 2D cultures. These properties are important for in-vitro modeling systems, as well as for in-vivo cell therapies and tissue engineering approaches. A reliable use of 3D cellular models still requires standardized protocols with well-controlled and reproducible parameters. To address this challenge, a robust and scaffold-free approach is proposed, which relies on multi-trap acoustic levitation. This technology is successfully applied to Mesenchymal Stromal Cells (MSCs) maintained in acoustic levitation over a 24-hour period. During the culture, MSCs spontaneously self-organized from cell sheets to cell spheroids with a characteristic time of about ten hours. Each acoustofluidic chip could contain up to 30 spheroids in acoustic levitation and four chips could be ran in parallel, leading to the production of 120 spheroids per experiment. Various biological characterizations showed that the cells inside the spheroids were viable, maintained the expression of their cell surface markers and had a higher differentiation capacity compared to standard 2D culture conditions. These results open the path to long-time cell culture in acoustic levitation of cell sheets or spheroids for any type of cells.; In recent years, 3D cell culture models such as spheroid or organoid technologies have known important developments. Many studies have shown that 3D cultures exhibit better biomimetic properties compared to 2D cultures. These properties are important for in-vitro modeling systems, as well as for in-vivo cell therapies and tissue engineering approaches. A reliable use of 3D cellular models still requires standardized protocols with well-controlled and reproducible parameters. To address this challenge, a robust and scaffold-free approach is proposed, which relies on multi-trap acoustic levitation. This technology is successfully applied to Mesenchymal Stromal Cells (MSCs) maintained in acoustic levitation over a 24-hour period. During the culture, MSCs spontaneously self-organized from cell sheets to cell spheroids with a characteristic time of about ten hours. Each acoustofluidic chip could contain up to 30 spheroids in acoustic levitation and four chips could be ran in parallel, leading to the production of 120 spheroids per experiment. Various biological characterizations showed that the cells inside the spheroids were viable, maintained the expression of their cell surface markers and had a higher differentiation capacity compared to standard 2D culture conditions. These results open the path to long-time cell culture in acoustic levitation of cell sheets or spheroids for any type of cells.

Published
2021

2. Osteogenic-differentiated Mesenchymal Stem Cell-secreted Extracellular Matrix as a Bone Morphogenetic Protein-2 delivery system for ectopic bone formation

Author

Esther Potier, Niclas Setterblad, M. Bensidhoum, Delphine Logeart-Avramoglou, Nathanaël Larochette, Hervé Petite, Hanane El-Hafci, Biologie, Bioingénierie et Bioimagerie Ostéo-articulaires (B3OA (UMR_7052)), Institut National de la Santé et de la Recherche Médicale (INSERM)-École nationale vétérinaire d'Alfort (ENVA)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Biologie, Bioingénierie et Bioimagerie Ostéo-articulaires (B3OA), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), and Logeart-Avramoglou, Delphine

Subjects
Bone Regeneration, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 0206 medical engineering, Biomedical Engineering, Bone Morphogenetic Protein 2, 02 engineering and technology, Biochemistry, Bone morphogenetic protein 2, Biomaterials, Extracellular matrix, Mice, Osteogenesis, In vivo, medicine, Extracellular, Animals, Bone regeneration, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Molecular Biology, Cells, Cultured, Decellularization, Chemistry, Growth factor, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, General Medicine, 021001 nanoscience & nanotechnology, 020601 biomedical engineering, dissemin, Extracellular Matrix, Cell biology, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, [SDV] Life Sciences [q-bio], [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, 0210 nano-technology, Biotechnology
Abstract

International audience; While human bone morphogenetic protein-2 (BMP-2) is a promising growth factor for bone regeneration, a major challenge in biomedical applications is finding an optimal carrier for its delivery at the site of injury. Because of their natural affinities for growth factors (including BMP-2) as well as their role in instructing cell function, cultured cell-derived extracellular matrices (ECM) are of special interest. We hereby hypothesized that a “bony matrix” containing mineralized, osteogenic ECM is a potential efficacious carrier of BMP-2 for promoting bone formation and, therefore, compared the efficacy of the decellularized ECM derived from osteogenic-differentiated human mesenchymal stem cells (hMSCs) to the one obtained from ECM from undifferentiated hMSCs. Our results provided evidence that both ECMs can bind BMP-2 and promote bone formation when implanted ectopically in mice. The osteoinductive potential of BMP-2, however, was greater when loaded within an osteogenic MSC-derived ECM; this outcome was correlated with higher sequestration capacity of BMP-2 over time in vivo. Interestingly, although the BMP-2 mainly bound onto the mineral crystals contained within the osteogenic MSC derived-ECM, these mineral components were not involved in the observed higher osteoinductivity, suggesting that the organic components were the critical components for the matrix efficacy as BMP-2 carrier.

Published
2020

3. A clinical‐grade acellular matrix for esophageal replacement

Author

Mohamed Jarraya, Niclas Setterblad, Jérôme Larghero, Valérie Vanneaux, Lousineh Arakelian, Camille Flageollet, Sara Shamdani, Patrick Bruneval, Sabrina Kellouche, Laurent Corté, Clémentine Caille, Thomas Domet, Pierre Cattan, Patricia Albanese, Lionel Faivre, Université Paris sciences et lettres (PSL), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Croissance, Réparation et Régénération Tissulaires (CRRET), EAC 7149-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Drexel University, Plate-forme d'imagerie, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe de recherche sur les relations matrice extracellulaire-cellules (ERRMECe), Fédération INSTITUT DES MATÉRIAUX DE CERGY-PONTOISE (I-MAT), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Cell Therapy Unit, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Thérapie Cellulaire, Hopital St Louis, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité)

Subjects
Pathology, medicine.medical_specialty, Swine, 0206 medical engineering, Biomedical Engineering, Medicine (miscellaneous), 02 engineering and technology, Matrix (biology), Biomaterials, Extracellular matrix, 03 medical and health sciences, chemistry.chemical_compound, Esophagus, Tissue engineering, Materials Testing, medicine, Animals, [CHIM]Chemical Sciences, Sodium dodecyl sulfate, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [PHYS]Physics [physics], 0303 health sciences, Decellularization, Tissue Engineering, Tissue Scaffolds, Chemistry, Stomach, Mesenchymal stem cell, Mesenchymal Stem Cells, 020601 biomedical engineering, Extracellular Matrix, medicine.anatomical_structure
Abstract

In pathologies of the esophagus such as esophageal atresia, cancers, and caustic injuries, methods for full thickness esophageal replacement require the sacrifice of healthy intra-abdominal organs such as the stomach and the colon and are associated with high morbidity, mortality, and poor functional results. To overcome these problems, tissue engineering methods are developed to create a substitute with scaffolds and cells. The aim of this study was to develop a simple and safe decellularization process in order to obtain a clinical grade esophageal extracellular matrix. Following the decontamination step, porcine esophagi were decellularized in a bioreactor with sodium dodecyl sulfate and ethylenediaminetetraacetic acid for 3 days and were rinsed with deionized water. DNA was eliminated by a 3-hr DNase treatment. To remove any residual detergent, the matrix was then incubated with an absorbing resin. The resulting porcine esophageal matrix was characterized by the assessment of the efficiency of the decellularization process (DNA quantification), evaluation of sterility and absence of cytotoxicity, and its composition and biomechanical properties, as well as the possibility to be reseeded with mesenchymal stem cells. Complete decellularization with the preservation of the general structure, composition, and biomechanical properties of the native esophageal matrix was obtained. Sterility was maintained throughout the process, and the matrix showed no cytotoxicity. The resulting matrix met clinical grade criteria and was successfully reseeded with mesenchymal stem cells..

Published
2019

4. EMMPRIN regulates β1 integrin-mediated adhesion through Kindlin-3 in human melanoma cells

Author

Céleste Lebbé, Suzanne Menashi, Julie Delyon, Niclas Setterblad, Farah Khayati, Samia Mourah, Ibtissem Djaafri, Kamel Maouche, Uwe Maskos, Marie-Pierre Podgorniak, Zineb Boutalbi, Aurélie Sadoux, Neurobiologie intégrative des Systèmes cholinergiques (NISC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Ligue Nationale contre le Cancer, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Société Française de Dermatologie (SFD), and by the Assistance Publique-Hôpitaux de Paris (APHP) as a Contrat Année-Recherche for JD., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurobiologie intégrative des Systèmes cholinergiques, and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
MESH: Signal Transduction, MESH: Antigens, CD29, MESH: Neoplasm Proteins, Skin Neoplasms, EMMPRIN, [SDV]Life Sciences [q-bio], Proximity ligation assay, Kindlin-3, Biochemistry, Extracellular matrix, Mice, [SCCO]Cognitive science, 0302 clinical medicine, MESH: RNA, Small Interfering, MESH: Animals, RNA, Small Interfering, 0303 health sciences, biology, Chemistry, Integrin beta1, Adhesion, MESH: Gene Expression Regulation, Neoplastic, Extracellular Matrix, Neoplasm Proteins, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Heterografts, Female, Integrin, beta 6, MESH: Membrane Proteins, Signal transduction, Signal Transduction, MESH: Cell Line, Tumor, MESH: Melanoma, Integrin, Mice, Nude, Dermatology, In Vitro Techniques, MESH: Extracellular Matrix, MESH: Cell Adhesion, Focal adhesion, 03 medical and health sciences, β1 integrin, Cell Line, Tumor, MESH: Antigens, CD147, melanoma, MESH: Mice, Nude, Animals, Humans, MESH: Cell Shape, Cell adhesion, Cell Shape, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: In Vitro Techniques, MESH: Humans, MESH: Skin Neoplasms, [SCCO.NEUR]Cognitive science/Neuroscience, Membrane Proteins, cell adhesion, MESH: Gene Knockdown Techniques, Basigin, biology.protein, MESH: Heterografts, MESH: Female
Abstract

International audience; EMMPRIN is known to promote tumor invasion through extracellular matrix (ECM) degradation. Here we report that EMMPRIN can regulate melanoma cell adhesion to the ECM through an interaction with β1 integrin involving kindlin-3. In this study, EMMPRIN knockdown in the human melanoma cell line M10 using siRNA decreased cell invasion and significantly increased cell adhesion and spreading. A morphological change from a round to a spread shape was observed associated with enhanced phalloidin-labelled actin staining. In situ proximity ligation assay and co-immunoprecipitation revealed that EMMPRIN silencing increased the interaction of β1 integrin with kindlin-3, a focal adhesion protein. This was associated with an increase in β1 integrin activation and a decrease in the phosphorylation of the downstream integrin kinase FAK. Moreover, the expression at both the transcript and protein level of kindlin-3 and of β1 integrin was inversely regulated by EMMPRIN. EMMPRIN did not regulate either talin expression or its interaction with β1 integrin. These results are consistent with our in vivo demonstration that EMMPRIN inhibition increased β1 integrin activation and its interaction with kindlin-3. To conclude, these findings reveal a new role of EMMPRIN in tumor cell migration through ß1 integrin/kindlin-3-mediated adhesion pathway.

Published
2015

5. Stem cells increase in numbers in perinecrotic areas in human renal cancer

Author

Arnaud Duval, Christophe Leboeuf, Jérôme Verine, Niclas Setterblad, Anne Janin, Guillaume Gapihan, Jean-Paul Feugeas, Pierre Mongiat-Artus, Irmine Ferreira, Philippe Ratajczak, Guilhem Bousquet, Mariana Varna, Sophie Tan, Stéphane Germain, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pathologie (Sorbonne Paris Cité / UNIV Paris Diderot), Université Paris Diderot, Sorbonne Paris Cité, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL), and Germain, Stéphane

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Indoles, Necrosis, Mice, Nude, Antineoplastic Agents, urologic and male genital diseases, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Renal cell carcinoma, Cancer stem cell, Sunitinib, medicine, Animals, Humans, Pyrroles, Carcinoma, Renal Cell, 030304 developmental biology, 0303 health sciences, business.industry, Therapeutic effect, Hypoxia (medical), medicine.disease, Xenograft Model Antitumor Assays, Kidney Neoplasms, In vitro, female genital diseases and pregnancy complications, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, medicine.symptom, Stem cell, business, medicine.drug
Abstract

Purpose: Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis–associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC. Experimental Design: We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4–coexpressing cells derived from the two responder xenograft models were used for in vitro studies. Results: In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4–coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4–coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased. Conclusions: In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers. Clin Cancer Res; 21(4); 916–24. ©2014 AACR.

Published
2015

6. Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome

Author

Niclas Setterblad, Marwan El-Sabban, Hiba El Hajj, Claudine Pique, Ali Bazarbachi, Alessia Zamborlini, Ali Saïb, Olivier Hermine, Zeina Dassouki, Youmna Kfoury, Department of Internal Medicine, American University of Beirut [Beyrouth] (AUB), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Department of Human Morphology, Pathologie et virologie moléculaire (PVM (UMR_7151)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), American University of Beirut [Beyrouth], IFR Saint-Louis, institut d'hématologie ( ISLIH ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pathologie et virologie moléculaire, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie et virologie moléculaire (PVM), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7) - Centre National de la Recherche Scientifique (CNRS), and BMC, Ed.

Subjects
Cytoplasm, SUMO protein, Fluorescent Antibody Technique, Plasma protein binding, Kidney, Bioinformatics, Biochemistry, Protein structure, Ubiquitin, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Lung, Cells, Cultured, health care economics and organizations, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, Chemistry, Reverse Transcriptase Polymerase Chain Reaction, 030302 biochemistry & molecular biology, NF-kappa B, Hematology, Gene Products, tax, I-kappa B Kinase, 3. Good health, Cell biology, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Signal transduction, Protein Binding, Signal Transduction, lcsh:Immunologic diseases. Allergy, Transcriptional Activation, Immunology, Blotting, Western, 03 medical and health sciences, Virology, Hum, Humans, RNA, Messenger, 030304 developmental biology, Cell Nucleus, Centrosome, 030306 microbiology, Ubiquitination, Sumoylation, Kidney metabolism, Cell Biology, Fibroblasts, Embryo, Mammalian, Molecular biology, Meeting Abstract, Ubiquitin-Conjugating Enzymes, biology.protein, lcsh:RC581-607, Protein Processing, Post-Translational
Abstract

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Published
2011

7. Ubiquitylated tax targets and binds the IKK signalosome at the centrosome

Author

Abdul G. Mikati, Niclas Setterblad, H El Hajj, Rihab Nasr, N. Renault, Ali Saïb, Estelle Chiari, Ali Bazarbachi, Claudine Pique, Marwan El-Sabban, Marie-Louise Giron, Youmna Kfoury, Olivier Hermine, A. Favre-Bonvin, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, IκB kinase, Plasma protein binding, Biology, environment and public health, chemistry.chemical_compound, Ubiquitin, Genetics, Humans, skin and connective tissue diseases, Molecular Biology, health care economics and organizations, Cell Line, Transformed, Centrosome, Human T-lymphotropic virus 1, Kinase, NF-κB, Gene Products, tax, I-kappa B Kinase, Cell biology, Enzyme Activation, Protein Subunits, enzymes and coenzymes (carbohydrates), Cytosol, chemistry, Cytoplasm, biology.protein, Transcriptional Elongation Factors, biological phenomena, cell phenomena, and immunity, Carrier Proteins, HeLa Cells, Protein Binding, Signal Transduction
Abstract

Constitutive activation of the NF-kappaB pathway by the Tax oncoprotein plays a crucial role in the proliferation and transformation of HTLV-I infected T lymphocytes. We have previously shown that Tax ubiquitylation on C-terminal lysines is critical for binding of Tax to IkappaB kinase (IKK) and its subsequent activation. Here, we report that ubiquitylated Tax is not associated with active cytosolic IKK subunits, but binds endogenous IKK-alpha, -beta, -gamma, targeting them to the centrosome. K63-ubiquitylated Tax colocalizes at the centrosome with IKK-gamma, while K48-ubiquitylated Tax is stabilized upon proteasome inhibition. Altogether, these results support a model in which K63-ubiquitylated Tax activates IKK in a centrosome-associated signalosome, leading to the production of Tax-free active cytoplasmic IKK. These observations highlight an unsuspected link between Tax-induced IKK activation and the centrosome.

Published
2008

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