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161 results on '"Seguin, Laetitia"'

1. A ganglioside-based immune checkpoint enables senescent cells to evade immunosurveillance during aging

Author

Iltis, Charlène, Moskalevska, Iryna, Debiesse, Antoine, Seguin, Laetitia, Fissoun, Christina, Cervera, Ludovic, Moudombi, Lyvia, Ardin, Maude, Ferrari, Anthony, Eliott, Coline, Pisani, Didier, Ottaviani, Alexandre, Bourinet, Manon, Luci, Carmelo, Gual, Philippe, Makulyte, Gabriela, Bernard, David, Durandy, Manon, Duret, Lou C., Hamidouche, Tynhinane, Kunz, Sarah, Croce, Olivier, Delannoy, Clément, Guérardel, Yann, Allain, Fabrice, Hofman, Paul, Benarroch-Popivker, Delphine, Bianchini, Laurence, Dadone-Montaudie, Berengère, Cosson, Estelle, Guglielmi, Julien, Pourcher, Thierry, Braud, Véronique M., Shkreli, Marina, Pers, Yves-Marie, Jorgensen, Christian, Brondello, Jean-Marc, Féral, Chloé C., Michallet, Marie-Cécile, Gilson, Eric, and Cherfils-Vicini, Julien

Published
2024
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2. A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function.

Author

Larange, Alexandre, Takazawa, Ikuo, Kakugawa, Kiyokazu, Thiault, Nicolas, Ngoi, SooMun, Olive, Meagan, Iwaya, Hitoshi, Seguin, Laetitia, Vicente-Suarez, Ildefonso, Becart, Stephane, Verstichel, Greet, Balancio, Ann, Altman, Amnon, Chang, John, Taniuchi, Ichiro, Lillemeier, Bjorn, Kronenberg, Mitchell, Myers, Samuel, and Cheroutre, Hilde

Subjects
FOXP3(+) regulatory T cells, T cell receptor, ZAP-70, anti-pathogen immunity, autoimmune disease, cellular-retinoic-acid-binding protein, effector differentiation, extranuclear, nuclear receptor, proliferation, retinoic acid, retinoic acid receptor alpha, signal transduction, Humans, Retinoic Acid Receptor alpha, Lymphocyte Activation, Autoimmune Diseases, Cell Membrane, Receptors, Antigen, T-Cell
Abstract

Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome. RA interfered with extranuclear RARα signaling, causing suboptimal TCR activation while enhancing FOXP3+ regulatory T cell conversion. TCR activation induced the expression of CRABP2, which translocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resulting in impaired anti-pathogen immunity and suppressed autoimmune disease. Our findings underscore the significance of subcellular RA/RARα signaling in T cells and identify extranuclear RARα as a component of the TCR signalosome and a determinant of immune responses.

Published
2023

5. Galectin-3, a druggable vulnerability for KRAS-addicted cancers

Author

Seguin, Laetitia, Camargo, Maria F, Wettersten, Hiromi I, Kato, Shumei, Desgrosellier, Jay S, von Schalscha, Tami, Elliott, Kathryn C, Cosset, Erika, Lesperance, Jacqueline, Weis, Sara M, and Cheresh, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Rare Diseases, Cancer, Pancreatic Cancer, Digestive Diseases, Orphan Drug, Lung, Lung Cancer, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Galectin 3, Humans, Lung Neoplasms, Mice, Signal Transduction, ras Proteins, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS-mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvβ3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvβ3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

Published
2017

6. Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

Author

Cosset, Érika, Ilmjärv, Sten, Dutoit, Valérie, Elliott, Kathryn, von Schalscha, Tami, Camargo, Maria F, Reiss, Alexander, Moroishi, Toshiro, Seguin, Laetitia, Gomez, German, Moo, Jung-Soon, Preynat-Seauve, Olivier, Krause, Karl-Heinz, Chneiweiss, Hervé, Sarkaria, Jann N, Guan, Kun-Liang, Dietrich, Pierre-Yves, Weis, Sara M, Mischel, Paul S, and Cheresh, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Biotechnology, Genetics, Stem Cell Research, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, Neurosciences, Brain Cancer, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Cancer, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Antineoplastic Agents, Brain Neoplasms, Cell Line, Tumor, Gene Expression Profiling, Glioblastoma, Glucose Transporter Type 3, Humans, Integrin alphaVbeta3, Kaplan-Meier Estimate, Mice, Mice, Nude, Signal Transduction, Snake Venoms, Transcriptome, Xenograft Model Antitumor Assays, Glut3, cancer stem cells, glioblastoma, glucose metabolism, integrin, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.

Published
2017

7. Glioblastomas Require Integrin αvβ3/PAK4 Signaling to Escape Senescence

Author

Franovic, Aleksandra, Elliott, Kathryn C, Seguin, Laetitia, Camargo, M Fernanda, Weis, Sara M, and Cheresh, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Brain Cancer, Neurosciences, Orphan Drug, Rare Diseases, Cancer, Brain Disorders, 2.1 Biological and endogenous factors, Animals, Brain Neoplasms, Cell Proliferation, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21, Female, Glioblastoma, Humans, Integrin alphaVbeta3, Mice, Mice, Nude, Neoplasm Transplantation, RNA Interference, RNA, Small Interfering, Signal Transduction, Spheroids, Cellular, Transplantation, Heterologous, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Vitronectin, p21-Activated Kinases, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin αvβ3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either αvβ3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, αvβ3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the αvβ3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.

Published
2015

8. Kinase-independent role for CRAF-driving tumour radioresistance via CHK2.

Author

Advani, Sunil J, Camargo, Maria Fernanda, Seguin, Laetitia, Mielgo, Ainhoa, Anand, Sudarshan, Hicks, Angel M, Aguilera, Joseph, Franovic, Aleksandra, Weis, Sara M, and Cheresh, David A

Subjects
Cell Line, Tumor, HCT116 Cells, Animals, Humans, Mice, DNA Damage, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, Serine, Fluorescent Antibody Technique, Immunoblotting, Xenograft Model Antitumor Assays, Immunoprecipitation, Neoplasm Transplantation, Phosphorylation, Mutation, Radiation, Ionizing, Radiation Tolerance, p21-Activated Kinases, Checkpoint Kinase 2, Cell Line, Tumor, Radiation, Ionizing, Cancer, Genetics, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, MD Multidisciplinary
Abstract

Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.

Published
2015

9. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance.

Author

Seguin, Laetitia, Desgrosellier, Jay S, Weis, Sara M, and Cheresh, David A

Subjects
Stromal Cells, Stem Cells, Humans, Neoplasms, Neoplasm Metastasis, Integrins, Cell Adhesion, Signal Transduction, Drug Resistance, cancer, drug resistance, integrins, stemness, stermness, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.

Published
2015

10. Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells

Author

Seguin, Laetitia, Odouard, Soline, Corlazzoli, Francesca, Haddad, Sarah Al, Moindrot, Laurine, Calvo Tardón, Marta, Yebra, Mayra, Koval, Alexey, Marinari, Eliana, Bes, Viviane, Guérin, Alexandre, Allard, Mathilde, Ilmjärv, Sten, Katanaev, Vladimir L., Walker, Paul R., Krause, Karl-Heinz, Dutoit, Valérie, Sarkaria, Jann N., Dietrich, Pierre-Yves, and Cosset, Érika

Published
2021
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11. A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

Author

Douguet, Laetitia, Janho dit Hreich, Serena, Benzaquen, Jonathan, Seguin, Laetitia, Juhel, Thierry, Dezitter, Xavier, Duranton, Christophe, Ryffel, Bernhard, Kanellopoulos, Jean, Delarasse, Cecile, Renault, Nicolas, Furman, Christophe, Homerin, Germain, Féral, Chloé, Cherfils-Vicini, Julien, Millet, Régis, Adriouch, Sahil, Ghinet, Alina, Hofman, Paul, and Vouret-Craviari, Valérie

Published
2021
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12. Targeting the Achilles’ heel of drug-resistant cancer stem cells

Author

Seguin, Laetitia, Gozo, Maricel, Weis, Sara M, and Cheresh, David A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Animals, Drug Resistance, Neoplasm, ErbB Receptors, Female, Humans, Integrin beta3, Lung Neoplasms, Neoplastic Stem Cells, Protein Kinase Inhibitors, Proto-Oncogene Proteins, ral GTP-Binding Proteins, ras Proteins, EGFR-TKI resistance, KRAS, NFkB, cancer stem cells, integrin β3, Developmental Biology, Biochemistry and cell biology
Published
2014

13. Variety in the Tumor Microenvironment: Integrin Splicing Regulates Stemness

Author

Seguin, Laetitia, Weis, Sara M, and Cheresh, David A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Immunology, Oncology and Carcinogenesis, Cancer, Breast Cancer, Stem Cell Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Female, Humans, Integrin alpha6, Neoplastic Stem Cells, RNA Splicing, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Recently in Cell Reports, Goel et al. (2014) identified mechanisms underlying cellular heterogeneity in triple negative breast cancer. They find that expression of α6 integrin and its splice variants differs between epithelial and mesenchymal tumor cell subpopulations, the latter of which relies on VEGF signaling to promote cancer stem cell function.

Published
2014

14. An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition

Author

Seguin, Laetitia, Kato, Shumei, Franovic, Aleksandra, Camargo, M Fernanda, Lesperance, Jacqueline, Elliott, Kathryn C, Yebra, Mayra, Mielgo, Ainhoa, Lowy, Andrew M, Husain, Hatim, Cascone, Tina, Diao, Lixia, Wang, Jing, Wistuba, Ignacio I, Heymach, John V, Lippman, Scott M, Desgrosellier, Jay S, Anand, Sudarshan, Weis, Sara M, and Cheresh, David A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Stem Cell Research - Nonembryonic - Human, Lung, Rare Diseases, Women's Health, Stem Cell Research, Lung Cancer, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Animals, Cell Line, Tumor, Cell Proliferation, Clinical Trials, Phase II as Topic, Drug Resistance, Neoplasm, ErbB Receptors, Erlotinib Hydrochloride, Female, Humans, Integrin alphaVbeta3, Integrin beta3, Lung Neoplasms, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Molecular Targeted Therapy, Neoplastic Stem Cells, Phenotype, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Proto-Oncogene Proteins p21(ras), Quinazolines, RNA Interference, Randomized Controlled Trials as Topic, Signal Transduction, Spheroids, Cellular, Time Factors, Transfection, Tumor Burden, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, ral GTP-Binding Proteins, ras Proteins, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)β₃ expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.

Published
2014

26. NANOBODY ® Molecule, a Giga Medical Tool in Nanodimensions.

Author

Kunz, Sarah, Durandy, Manon, Seguin, Laetitia, and Feral, Chloe C.

Subjects
SMALL molecules, MONOCLONAL antibodies, RECOMBINANT microorganisms, THROMBOPENIC purpura, MOLECULES, CHEMICAL resistance
Abstract

Although antibodies remain the most widely used tool for biomedical research, antibody technology is not flawless. Innovative alternatives, such as Nanobody® molecules, were developed to address the shortcomings of conventional antibodies. Nanobody® molecules are antigen-binding variable-domain fragments derived from the heavy-chain-only antibodies of camelids (VHH) and combine the advantageous properties of small molecules and monoclonal antibodies. Nanobody® molecules present a small size (~15 kDa, 4 nm long and 2.5 nm wide), high solubility, stability, specificity, and affinity, ease of cloning, and thermal and chemical resistance. Recombinant production in microorganisms is cost-effective, and VHH are also building blocks for multidomain constructs. These unique features led to numerous applications in fundamental research, diagnostics, and therapy. Nanobody® molecules are employed as biomarker probes and, when fused to radioisotopes or fluorophores, represent ideal non-invasive in vivo imaging agents. They can be used as neutralizing agents, receptor-ligand antagonists, or in targeted vehicle-based drug therapy. As early as 2018, the first Nanobody®, Cablivi (caplacizumab), a single-domain antibody (sdAb) drug developed by French pharmaceutical giant Sanofi for the treatment of adult patients with acquired thrombocytopenic purpura (aTTP), was launched. Nanobody® compounds are ideal tools for further development in clinics for diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

Published
2023
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28. A ganglioside-based senescence-associated immune checkpointARTICLE EN REVISION FAVORABLE DANS NATURE AGING

Author

Iltis, Charlène, Seguin, Laetitia, Cervera, Ludovic, Duret, Lou, Hamidouche, Tynhinane, Kunz, Sarah, Croce, Olivier, Delannoy, Clément, Gueŕardel, Yann, Allain, Fabrice, Moudombi, Lyvia, Hofman, Paul, Cosson, Estelle, Guglielmi, Julien, Pourcher, Thierry, Braud, Véronique, Shkreli, Marina, Michallet, Marie-Cécile, Feral, Chloé, Gilson, Eric, Cherfils-Vicini, Julien, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), UMR E4320 (TIRO-MATOs), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)

Subjects
[SDV]Life Sciences [q-bio], lipids (amino acids, peptides, and proteins)
Abstract

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging 1-4 . Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases 5 . As cells of the immune system are responsible for senescent cell elimination 6-11 , a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

Published
2021

29. A MEK-independent role for CRAF in mitosis and tumor progression

Author

Mielgo, Ainhoa, Seguin, Laetitia, Huang, Miller, Camargo, Maria Fernanda, Anand, Sudarshan, Franovic, Aleksandra, Weis, Sara M., Advani, Sunil J., Murphy, Eric A., and Cheresh, David A.

Subjects
Tumors -- Physiological aspects -- Growth, Mitosis -- Physiological aspects, Phosphotransferases -- Physiological aspects, Company growth, Biological sciences, Health
Abstract

RAF kinases regulate cell proliferation and survival and can be dysregulated in tumors (1,2). The role of RAF in cell proliferation has been linked to its ability to activate mitogen-activated protein kinase kinase 1 (MEK) and mitogen-activated protein kinase 1 (ERK). Here we identify a MEK-independent role for RAF in tumor growth. Specifically, in mitotic cells, CRAF becomes phosphorylated on Ser338 and localizes to the mitotic spindle of proliferating tumor cells in vitro as well as in murine tumor models and in biopsies from individuals with cancer. Treatment of tumors with allosteric inhibitors, but not ATP-competitive RAF inhibitors, prevents CRAF phosphorylation on Ser338 and localization to the mitotic spindle and causes cell-cycle arrest at prometaphase. Furthermore, we identify phospho-Ser338 CRAF as a potential biomarker for tumor progression and a surrogate marker for allosteric RAF blockade. Mechanistically, CRAF, but not BRAF, associates with Aurora kinase A (Aurora-A) and Polo-like kinase 1 (Plk1) at the centrosomes and spindle poles during G2/M. Indeed, allosteric or genetic inhibition of phosphoSer338 CRAF impairs Plk1 activation and accumulation at the kinetochores, causing prometaphase arrest, whereas a phospho-mimetic Ser338D CRAF mutant potentiates Plk1 activation, mitosis and tumor progression in mice. These findings show a previously undefined role for RAF in tumor progression beyond the RAF-MEK-ERK paradigm, opening new avenues for targeting RAF in cancer., ATP-competitive RAF inhibitors have been shown to have clinical activity in cancers with activating RAF alterations (3-8). However, in RAS-driven tumors, these agents promote CRAF Ser338 phosphorylation and tumor progression [...]

Published
2011
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30. Influenza vaccination and prognosis of COVID ‐19 in hospitalized patients with diabetes: Results from the CORONADO study

Author

Diallo, A, Pichelin, Matthieu, Wargny, Matthieu, Gourdy, Pierre, Bonnet, JB, Hadjadj, Samy, Cariou, Bertrand, Sultan, Ariane, Galtier, Florence, Mahot, Pascale, Fournier‐Guilloux, Anne‐Laure, Mauduit, Nicolas, Bigot‐corbel, Edith, Boureau, Anne‐Sophie, Dekcer, Laure, Ernould, Audrey, Primot, Claire, Seguin, Anne, Joliveau, Marielle, Pouvreau, Sonia, FOURNIER, Chloé, Thureau, Jeremy, Fonteneau, Edith, Hublain, Pamela, Nantes, Chu, Agasse, Carole, Kergaradec, Mathilde DE, Minville, Vincent, Vardon‐Bounes, Fanny, Martin‐Blondel, Guillaume, Tramunt, Blandine, Turnin, Marie‐Christine, Hanaire, Hélène, Mansuy, Jean‐Michel, Fabre, Didier, Arhainx, Marie‐Blanche, Cazals, Laurent, Combes, Laure, Lami, Emmanuelle, Cianferani, Mallory, Megarbane, Bruno, Leroy, Pierre, Gautier, Jean‐François, Vidal‐Trecan, Tiphaine, Riveline, Jean‐Pierre, Laplanche, Jean‐Louis, Mouly, Stéphane, Potier, Louis, Roussel, Ronan, Taher, Malak, Abouleka, Yawa, Yaker, Fetta, Carlier, Aurelie, Boutten, Anne, Hallot‐Feron, Marilyne, Mourah, Fadila, Thivolet, Charles, Blond, Emilie, Rolland, Muriel, Mendez, Josep Verdecho, Alexandre, Marine, Pottecher, Julien, Richer, Emilie, Meyer, Laurent, Luca, Florina, Lessinger, Jean‐Marc, Bahougne, Thibault, Guerci, Bruno, Ludwig, Lisa, Benzirar, Siham, Malaplate, Catherine, Matton, Thierry, Poissy, Julien, Faure, Karine, Fontaine, Pierre, Baudoux, Florence, Vambergue, Anne, Pekar, Jean David, Lambert, Marc, Yelnik, Cécile, Bruandet, Amélie, Petit, Laurent, Neau, Didier, Rigalleau, Vincent, Berard, Annie, Galioot, Amandine, Coudroy, Remy, Thille, Arnaud, Robert, René, Roblot‐Cazenave, France, Rammaert, Blandine, Saulnier, Pierre Jean, Piguel, Xavier, Benhenda, Nesrine, Husson, Camille, Olivier, Celine, Torremocha, Florence, Fraty, Mathilde, d'assigny, Marie Flamen, Miot, Aurelie, Bossard, Valentin, Klouche, Kada, Makinson, Alain, Bonnet, Jean‐Baptiste, Foulongne, Vincent, Aubron, Cécile, Ansart, Séverine, Kerlan, Véronique, Quiniou, Pascale, Carre, Jean‐Luc, Quesnot, Stéphane, Laviolle, Bruno, Schwebel, Carole, Epaulard, Olivier, Benhamou, Pierre‐Yves, Betry, Cécile, Borel, Anne‐Laure, Lablanche, Sandrine, Guergour, Dorra, Duclos, Catherine, Cosson, Emmanuel, Guyot, Erwan, Deniau, Aurore, Nguyen, Phucthutrang, Reznik, Yves, Joubert, Michael, Allouche, Stéphane, Guittet, Lydia, Grange, Steven, Etienne, Manuel, Prévost, Gaëtan, Brunel, Valéry, Lagier, Jean‐Christophe, Raoult, Didier, Dutour, Anne, Gaborit, Bénédicte, Boulllu, Sandrine, Darmon, Patrice, Lasbleiz, Adèle, Cerino, Mathieu, Romain, Fanny, Houssays, Marie, Quenot, Jean Pierre, Piroth, Lionel, Vergès, Bruno, Duvillard, Laurence, Bonnotte, Bernard, Mercat, Alain, Dubee, Vincent, Allix, Ingrid, Rodien, Patrice, Dhersin, Robin, Lebeault, Maylis, Trzepizur, Wojciech, Loison, Jocelyne, Brangier, Antoine, Asfar, Pierre, Reynier, Pascal, Larcher, Françoise, Joubaud, Françoise, Andreu, Marie‐Rita, Urbanski, Geoffrey, Hubert, Laurent, Annweiler, Cedric, Dellamonica, Jean, Courjon, Johan, Chevalier, Nicolas, Chinetti, Giulia, Chafai, Magda, Mourvillier, Bruno, Bani‐Sadr, Firouze, Barraud, Sarra, Delemer, Brigitte, Gillery, Philippe, Labedade, Pascale, Chabrol, Amélie, Penfornis, Alfred, Petit, Catherine, Amadou, Coralie, Adler, Maxime, Dubost, Clément, Conan, Pierre‐Louis, Bordier, Lyse, Ceppa, Franck, Garcia, Cyril, Sollier, Mathilde, Dupuy, Olivier, Laplance, Sophie, Billuart, Olivier, Aroulanda, Marie Joseph, Olivier, Frédérique, Ayon, Florence, Wilhelm, Nathalie, Epelboin, Loic, Sabbah, Nadia, Charpin, Aurelie, Squara, Pierre, Belliard, Olivier, Dubois, Claude, Marre, Michel, Auchabie, Johann, Courtois, Roxane, Duriez, Thierry, Mergey, Tiphaine, Vallee, Laura, Seguin, Laetitia, Al‐Salameh, Abdallah, Lanoix, Jean‐Philippe, Soriot‐Thomas, Sandrine, Bourgeois‐Descouls, Anne‐Marie, Desailloud, Rachel, Germain, Natacha, Galusca, Bogdan, Belleton, Gwenaelle, Marouani, Nesrine, Palaghiu, Delia, Hammour, Amira, Berdaguer, Fernando, Klopfenstein, Thimothée, Zayet, Hajer, Winiszewski, Patrice, Zanusso, Marie, Garnier, Pauline, Julier, Ingrid, Hamzaoui, Karim, Marty‐Gres, Sophie, Sadki, Tarik, Cadot, Lucile, Dubost, Jean‐Louis, Gonfroy, Céline, Campinos, Catherine, Martres, Pascale, Coulhon, Marie Pierre, Allou, Nicolas, Bachir, Marwa, Hoang, Stella, Kembellec, Candice, Suply, Olivia, Kharcha, Fatima, Devouge, Anne‐Claire, Flaus‐Furmanuk, Anna, Madeline, Isabelle, Ehinger, Vincent, Bastard, Sophie, Raffray, Loic, Renou, Frederic, Bojarski, Aude, Paul, Caroline, Borsu, Karine, Gorlin, Angelique, Bernardo, Servane, Ut, Carole Truong, Renaud, Stephane, Vignoles, Antoine, Foch, Emilie, Masse, Laurie, Grand, Hubert, Ferrand, Helene, Raffaitin‐Cardin, Christelle, Zellagui, Hadjer, Castang‐Brachet, Celine, Boury, Frederique, Tena, Ana Alvarez, Moura, Isabelle, Kalfon, Pierre, Darasteanu, Juliana, Monier, Arnaud, Foucault, Pascal, Depuille, Alexandra, Laugier‐Robiolle, Stéphanie, Caneiro, Patrick, Basso, Maud, Larger, Etienne, Bouam, Samir, Benzenati, Wahiba, Bachir, Leila Ait, Pillegand, Camille Cussac, Vasse, Marc, Michard, Christophe, Montanier, Nathanaëlle, Millot, Luc, Crepet, Françoise, Ratsimba, Danielle, Bouiller, Kevin, Borot, Sophie, Bruckert, Isabelle, Clergeot, Annie, Schillo, Franck, Vignes, Dorothée, Bourgeon‐Ghittori, Muriel, Lachgar, Hamoud, Cursay, Claire Lambert DE, Levante, Stéphane, Auregan, Jean Charles, Merlet, Antoine, Zaragoza, Cécile, Arnault, Gwénaëlle, Loupp, Anne‐Gaëlle, Lesieur, Olivier, Roncato‐Saberan, Mariam, Gouet, Didier, Lemarie, Romain, Allano, Hong_an, Vivier, Emmanuel, Pariset, Caroline, Luyton, Cédric, Marchand, Lucien, Doroszewski, Fanny, Pecquet, Matthieu, Perard, Laurent, Vuillermoz‐Blas, Sylvie, Kacki, Nicolas, Charrier, Patricia, Ducet‐Boiffard, Amélie, Roure, Françoise Desroys, Bourron, Olivier, Bonnefont‐Rousselot, Dominique, Laroche, Suzanne, Phan, Franck, Hartemann, Agnès, CAUSSY, Cyrielle, Disse, Emmanuel, Guerin, Claude, Perpoint, Thomas, Moulin, Philippe, CARTIER, RÉGINE, Hariri, Geoffroy, Chopin, Dorothée, Vatier, Camille, Bourcigaux, Nathalie, Chaigneau, Emmanuelle, Christin‐Maitre, Sophie, Donadille, Bruno, Feve, Bruno, Lamothe, Sophie, Sarfati, Julie, Pernet, Pascal, Chambon, Anne, Demarsy, Delphine, Campagne, Hugo, Latil‐Plat, Françoise, Berne, Monica, Grinand, Marilyne, Touzet, Marion, Zabulon, Aydrey, Craspag, Jocelyne, Ledoux, Catherine, Contaret, Cedric, Janand‐Delenne, Blandine, Giraud, Anaïs, Lacrimini, Marie Lou, Arrivie, Joëlle, Ancelle, Deborah, Guillois, Carine, Fremy, Bénédicte, Chaalal, Amina, Barrande, Gaëlle, Dorange, Anne, Rouanet, Eglantine, Seret‐Begue, Dominique, Saoud, Audrey, Guedj, Anne‐Marie, Bedos, Nathalie, Velayoudom, Fritz‐Line, Dumas, Marie, Gonda, Benoite, Coffin, Christine, Gibiat, Stéphanie, Lungo, Myriam, Bully, Chantal, Serusclat, Pierre, Bully, Stella, Carre, Patricia, Leberre, Jean‐Philippe, Elkhoury, Carlos, THIEUX, Marine, Paradisi‐Prieur, Laetitia, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Hospitalized patients, Influenza vaccine, Endocrinology, Diabetes and Metabolism, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, Influenza, Human, Internal Medicine, Diabetes Mellitus, Research Letter, Medicine, Humans, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, SARS-CoV-2, Vaccination, COVID-19, medicine.disease, Prognosis, Research Letters, 3. Good health, Hospitalization, Propensity score matching, business
Abstract

International audience

Published
2021
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31. A ganglioside-based senescence-associated immune checkpoint

Author

Iltis, Charlène, primary, Seguin, Laetitia, additional, Cervera, Ludovic, additional, Duret, Lou, additional, Hamidouche, Tynhinane, additional, Kunz, Sarah, additional, Croce, Olivier, additional, Delannoy, Clément, additional, Gueŕardel, Yann, additional, Allain, Fabrice, additional, Moudombi, Lyvia, additional, Hofman, Paul, additional, Cosson, Estelle, additional, Guglielmi, Julien, additional, Pourcher, Thierry, additional, Braud, Véronique M., additional, Shkreli, Marina, additional, Michallet, Marie-Cécile, additional, Feral, Chloé C., additional, Gilson, Eric, additional, and Cherfils-Vicini, Julien, additional

Published
2021
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33. Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge

Author

Douguet, Laetitia, primary, dit Hreich, Serena Janho, additional, Benzaquen, Jonathan, additional, Seguin, Laetitia, additional, Juhel, Thierry, additional, Dezitter, Xavier, additional, Duranton, Christophe, additional, Ryffel, Bernhard, additional, Kanellopoulos, Jean, additional, Delarasse, Cecile, additional, Renault, Nicolas, additional, Furman, Christophe, additional, Homerin, Germain, additional, Féral, Chloé, additional, Cherfils-Vicini, Julien, additional, Millet, Régis, additional, Adriouch, Sahil, additional, Ghinet, Alina, additional, Hofman, Paul, additional, and Vouret-Craviari, Valérie, additional

Published
2020
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34. Extra-Nuclear and Nuclear Rarα Reciprocally Control Tcr-Induced Proliferation and Differentiation

Author

Larange, Alexandre, primary, Kakugawa, Kiyokazu, additional, Takazawa, Ikuo, additional, Iwaya, Hitoshi, additional, Ngoi, SooMun, additional, Seguin, Laetitia, additional, Vicente-Suarez, Ildefonso, additional, Thiault, Nicolas, additional, Becart, Stephane, additional, Lena, Christopher, additional, Huang, Yujun, additional, Feau, Sonia, additional, Shui, Jr-Wen, additional, Schmiedel, Benjamin J., additional, Altman, Amnon, additional, Peters, Bjoern, additional, Vijayanand, Pandurangan, additional, Lillemeier, Bjorn, additional, Chang, John T., additional, Taniuchi, Ichiro, additional, Kronenberg, Mitchell, additional, and Cheroutre, Hilde, additional

Published
2019
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38. Abstract 1916: β3 integrin/KRAS/RalB complex drives tumor stemness and resistance to EGFR inhibition

Author

Seguin, Laetitia Jocelyne, primary, Kato, Shumei, additional, Franovic, Aleksandra, additional, Camargo, Maria Fernanda, additional, Elliott, Katrhyn, additional, Yebra, Mayra, additional, Lesperance, Jacqueline, additional, Mielgo, Ainhoa, additional, Desgrosellier, Jay, additional, Anand, Sudarshan, additional, Weis, Sara, additional, and Cheresh, David, additional

Published
2014
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50. Corrigendum to “Phosphoregulation of MgcRacGAP in mitosis involves Aurora B and Cdk1 protein kinases and the PP2A phosphatase” [FEBS Lett. 582 (2008) 1182-1188]

Author

Touré, Aminata, primary, Mzali, Rym, additional, Liot, Caroline, additional, Seguin, Laetitia, additional, Morin, Laurence, additional, Crouin, Catherine, additional, Chen-Yang, Ilin, additional, Tsay, Yeou-Guang, additional, Dorseuil, Olivier, additional, Gacon, Gérard, additional, and Bertoglio, Jacques, additional

Published
2008
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