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19 results on '"Mamy Andrianteranagna"'

1. Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups

Author

María-Jesús Lobón-Iglesias, Mamy Andrianteranagna, Zhi-Yan Han, Céline Chauvin, Julien Masliah-Planchon, Valeria Manriquez, Arnault Tauziede-Espariat, Sandrina Turczynski, Rachida Bouarich-Bourimi, Magali Frah, Christelle Dufour, Thomas Blauwblomme, Liesbeth Cardoen, Gaelle Pierron, Laetitia Maillot, Delphine Guillemot, Stéphanie Reynaud, Christine Bourneix, Célio Pouponnot, Didier Surdez, Mylene Bohec, Sylvain Baulande, Olivier Delattre, Eliane Piaggio, Olivier Ayrault, Joshua J. Waterfall, Nicolas Servant, Kevin Beccaria, Volodia Dangouloff-Ros, and Franck Bourdeaut

Subjects
Science
Abstract

Abstract Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-CreERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway.

Published
2023
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2. Diagnostic accuracy of a minimal immunohistochemical panel in at/rt molecular subtyping, correlated to dna-methylation profiling

Author

Arnault Tauziède-Espariat, Julien Masliah-Planchon, Mamy Andrianteranagna, Philipp Sievers, Felix Sahm, Andreas von Deimling, Lauren Hasty, Olivier Delattre, Kévin Beccaria, Alice Métais, Fabrice Chrétien, Pascale Varlet, and Franck Bourdeaut

Subjects
AT/RT, DNA-methylation profiling, TYR, SHH, MYC, Immunohistochemistry., Neurology. Diseases of the nervous system, RC346-429
Published
2023
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3. An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

Author

Morgane Morabito, Magalie Larcher, Florence MG Cavalli, Chloé Foray, Antoine Forget, Liliana Mirabal‐Ortega, Mamy Andrianteranagna, Sabine Druillennec, Alexandra Garancher, Julien Masliah‐Planchon, Sophie Leboucher, Abel Debalkew, Alessandro Raso, Olivier Delattre, Stéphanie Puget, François Doz, Michael D Taylor, Olivier Ayrault, Franck Bourdeaut, Alain Eychène, and Celio Pouponnot

Subjects
activin, medulloblastoma, Smad2, Smad3, TGFbeta, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB‐PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

Published
2019
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4. High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors

Author

Céline Chauvin, Amaury Leruste, Arnault Tauziede-Espariat, Mamy Andrianteranagna, Didier Surdez, Aurianne Lescure, Zhi-Yan Han, Elodie Anthony, Wilfrid Richer, Sylvain Baulande, Mylène Bohec, Sakina Zaidi, Marie-Ming Aynaud, Laetitia Maillot, Julien Masliah-Planchon, Stefano Cairo, Sergio Roman-Roman, Olivier Delattre, Elaine Del Nery, and Franck Bourdeaut

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Rhabdoid tumors (RTs) are aggressive tumors of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRα/β and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs. : Rhabdoid tumors (RTs) are aggressive pediatric tumors characterized by SMARCB1 inactivation. Chauvin et al. identify two SMARCB1-dependent targeted therapies for RT: pazopanib, which inhibits PDGFR and FGFR2, and the potassium channel inhibitor clofilium tosylate, which induces endoplasmic reticulum stress. Combining both drugs induces cell apoptosis and reduces PDX tumor growth. Keywords: rhabdoid tumors, SMARCB1, pazopanib, clofilium tosylate, high-throughput drug screening, tyrosine kinase inhibitors

Published
2017
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5. <scp>SMARCA4</scp> ‐deficient rhabdoid tumours show intermediate molecular features between <scp>SMARCB1</scp> ‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

Author

Noëlle Weingertner, Amaury Leruste, Daniel Orbach, Nicolas Servant, Franck Bourdeaut, Uwe Kordes, Gaëlle Pierron, Nadège Corradini, Dominique Ranchère, Alexandra Leary, Alice Corsia, Ulrich Schüller, Joanna Cyrta, Michael C. Frühwald, Mamy Andrianteranagna, Dörthe Holdhof, Karolina Nemes, Olivier Delattre, Paul Fréneaux, Jonathan W. Bush, Julien Masliah-Planchon, Anne Brouchet, Natacha Entz-Werle, and Marie-Pierre Castex

Subjects
Male, 0301 basic medicine, Biology, Malignancy, Pathology and Forensic Medicine, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Epigenetics, Carcinoma, Small Cell, SMARCB1, Rhabdoid Tumor, Ovarian Neoplasms, DNA Helicases, Infant, Nuclear Proteins, SMARCB1 Protein, Methylation, medicine.disease, Pediatric cancer, 030104 developmental biology, Child, Preschool, 030220 oncology & carcinogenesis, DNA methylation, SMARCA4, Cancer research, Female, Transcription Factors
Abstract

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2021
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6. Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

Author

Annie Huang, Julien Masliah-Planchon, Ben Ho, Anne Bendel, Santhosh A. Upadhyaya, Sepehr Safaei, David Creytens, Marcel Kool, Uwe Kordes, Ulrich Schüller, Daniela Indenbirken, Michael C. Frühwald, Piyush Joshi, William D. Foulkes, Mamy Andrianteranagna, Michael Bockmayr, Pascal Johann, Martin Hasselblatt, Dörthe Holdhof, Jonathan W. Bush, Michael Spohn, and Franck Bourdeaut

Subjects
HYPOMETHYLATION, CHILDREN, VARIANTS, medicine.disease_cause, ATRT, Central Nervous System Neoplasms, Transcriptome, BRG1, SMARCA4, Medicine and Health Sciences, Age of Onset, SMARCB1, Child, Mutation, DNA methylation, Teratoma, Nuclear Proteins, RNA sequencing, RHABDOID TUMORS, SMARCB1 Protein, Middle Aged, Child, Preschool, Adult, Adolescent, Clinical Neurology, HYPERCALCEMIC TYPE, Biology, Pathology and Forensic Medicine, Young Adult, Cellular and Molecular Neuroscience, Germline mutation, Rhabdoid, SMALL-CELL-CARCINOMA, medicine, Humans, SUBGROUPS, ddc:610, Gene, Rhabdoid Tumor, Medulloblastoma, Original Paper, COMPLEX, Gene Expression Profiling, DNA Helicases, Computational Biology, Biology and Life Sciences, medicine.disease, Survival Analysis, OVARY, Cancer research, Neurology (clinical), Transcription Factors
Abstract

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

Published
2020
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7. AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia

Author

Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal, Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed, Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick Auberger, Andrew A. Lane, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, and Jerome Tamburini

Subjects
Adult, Male, Adolescent, THP-1 Cells, Citric Acid Cycle, Drug Evaluation, Preclinical, Antineoplastic Agents, Apoptosis, HL-60 Cells, Pyrimidinones, AMP-Activated Protein Kinases, General Biochemistry, Genetics and Molecular Biology, Oxidative Phosphorylation, Mice, Young Adult, eIF-2 Kinase, Cell Line, Tumor, Animals, Humans, Aged, Aged, 80 and over, Sulfonamides, Imidazoles, U937 Cells, Middle Aged, Bridged Bicyclo Compounds, Heterocyclic, Mitochondria, Leukemia, Myeloid, Acute, HEK293 Cells, Proto-Oncogene Proteins c-bcl-2, Unfolded Protein Response, Female
Abstract

AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.

Published
2021

8. ATRT-11. Anatomico-biological correlations define a new layer for ATRT molecular subgroups pointing to potential lineages of origin

Author

Maria Lobon-Iglesias, Mamy Andrianteranagna, Zhi-Yan Han, Julien Masliah-Planchon, Arnault Tauziede-Espariat, Magali Frah, Christelle Dufour, Celine Chauvin, Rachida Bouarich, Valeria Manriquez, Sandrina Turczinski, Olivier Delattre, Sylvain Baulande, Olivier Ayrault, Nicolas Servant, Kevin Beccaria, Volodia Dangouloff-Ros, and Franck Bourdeaut

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

Atypical teratoid rhabdoid tumors (ATRT) are divided in three molecular subgroups, the so-called MYC, TYR and SHH subgroups. This heterogeneity suggests some diversity in the cells of origin, which remain hypothetical thus far. A careful radiological review of 55 MRI at diagnosis was performed in parallel with a careful analysis of mouse tumor origin in the Rosa26-CreERT2::Smarcbflox/flox model. Methylation, bulk RNAseq and scRNAseq analyses were integrated to these anatomic information to highlight potential origin for each molecularly and anatomically defined subgroups. We demonstrated that mouse Myc-ATRTs derive from extra-parenchymal meningeal areas, a finding consistant with many human MYC ATRT being clearly of intra-cranial extra-axial origin. Although this finding could point to a neural crest origin, transcriptomic features fail to unravel any lineage-specific signature. We also defined a distinct supra-tentorial SHH ATRT subgroup, characterized both in mouse and Humans by neural features pointing to the ganglionic eminence progenitors as the candidate origin. Finally we identified a distinct infra-tentorial SHH ATRT subgroup, not observed in mice, with hindbrain/midbrain boundary progenitor signature. scRNAseq from human SHH infra-tentorial tumors consistently suggest a dedifferentiation process involving the Notch pathway in the oncogenic transformation of hindbrain/midbrain neural progenitors.

Published
2022
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9. Network-Based Integration of Multi-Omics Data Identifies the Determinants of miR-491-5p Effects

Author

Mamy Andrianteranagna, Emilie Brotin, Emmanuel Barillot, Mégane Vernon, Edwige Abeilard, Loredana Martignetti, Nicolas Vigneron, Jean-Paul Issartel, Damarys Loew, Célia Brochen, Anaïs Wambecke, Matthieu Meryet-Figuière, Florent Dingli, Pascal Gauduchon, Audrey Guttin, Christophe Denoyelle, Laurent Poulain, and Bernard Lambert

Subjects
Cancer Research, Microarray analysis techniques, Computer science, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Computational biology, multi-omics, Phenotype, Article, ovarian cancer, Oncology, Interaction network, network, microRNA, Multi omics, Identification (biology), miR-491-5p, RC254-282, miRNA
Abstract

Simple Summary The re-introduction of miRNAs with tumor-suppressor activity in cancer cells has not yet been implemented in clinical practice yet. However, the identification of miRNAs’ targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA’s effects. We devised a multi-omics approach to precisely characterize the effects of miR-491-5p, a cytotoxic miRNA in ovarian cancer cells, and performed an integrated network analysis. We identified the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases—either direct or indirect targets of miR-491-5p—as regulatory hubs for miR-491-5p-mediated effects. Targeting different combinations of these hubs with specific inhibitors mimic miR-491-5p-induced cytotoxicity. Pharmacological inhibitors of these targets are available for clinical use or in clinical trials; thus, this study might enable innovative therapeutic options for ovarian cancer, the leading cause of death from gynecological malignancies in developed countries. Abstract The identification of miRNAs’ targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA’s effects. Based on this assumption we devised a multi-omics approach to precisely characterize miRNAs’ effects. We combined miR-491-5p target affinity purification, RNA microarray, and mass spectrometry to perform an integrated analysis in ovarian cancer cell lines. We thus constructed an interaction network that highlighted highly connected hubs being either direct or indirect targets of miR-491-5p effects: the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases. By using different combinations of specific inhibitors of these hubs, we could greatly enhance their respective cytotoxicity and mimic the miR-491-5p-induced phenotype. Our methodology thus constitutes an interesting strategy to comprehensively study the effects of a given miRNA. Moreover, we identified targets for which pharmacological inhibitors are already available for a clinical use or in clinical trials. This study might thus enable innovative therapeutic options for ovarian cancer, which remains the leading cause of death from gynecological malignancies in developed countries.

Published
2021
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10. Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Author

Sonia Lameiras, Pamela Caudana, Sylvain Baulande, Arnault Tauziède-Espariat, Nicolas Servant, Franck Bourdeaut, Amaury Leruste, Joshua J. Waterfall, Didier Surdez, Mamy Andrianteranagna, Stéphanie Puget, Sandrine Grossetête-Lalami, Eliane Piaggio, Christine Sedlik, Jimena Tosello, Mylène Bohec, Philippe Benaroch, Rodrigo Nalio Ramos, Celio Pouponnot, Jovan Nikolic, Julie Helft, Solene Brohard, Valeria Manriquez, Louise Galmiche, Leticia Laura Niborski, Olivier Delattre, Aurore Coulomb, Zhi-Yan Han, Céline Chauvin, Kevin Beccaria, Julien Masliah-Planchon, Wilfrid Richer, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathology Department [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Gene and Cell Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité, Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, This work was funded by the BMS and the Janssen Horizon Foundations, the Société Française des Cancers de l’Enfant (SFCE) with the associations 'Enfants et Santé' and 'L’Étoile de Martin,' INCA PL-BIO 2016 call for Project from the French Minister of Research, the 'Abigael,' 'ADAM,' 'Au Nom d’Andréa,' and 'Marabout de Ficelles' associations. RTOP team is supported by the SiRIC-Curie Program (grant INCa-DGOS-4654). INSERM U830 is supported by the Institut National de la Santé et de la Recherche Médicale, Curie Institute and the Ligue Nationale Contre Le Cancer. TransImm team is supported by the SiRIC-Curie Program (grant INCa-DGOS-12554), the LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), and the Center of Clinical Investigation (CIC IGR-Curie 1428). A.L. and P.C. were supported by the PhD program of Curie Institute., The authors thank S. Cairo, M. Chicard, J. Denizeau, C. Goudot, P. Gueguen, I. Jimenez, N. Manel, A. Pinto, S. Viel, S. Zaidi, and the mouse and the cytometry facility cores at Curie Institute., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), PSL Research University (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), and Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], SMARCB1, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, single-cell RNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Immune system, endogenous retrovirus, medicine, Animals, Humans, tumor immunology, AT/RT, rhabdoid tumor, Immunogenicity, T-cell receptor, Nuclear Proteins, Cell Biology, Immunotherapy, Chromatin Assembly and Disassembly, Pediatric cancer, Immunohistochemistry, SWI/SNF, 3. Good health, Chromatin, pediatric cancer, DNA-Binding Proteins, Mice, Inbred C57BL, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, immunotherapy, T cell receptor, CD8, Transcription Factors
Abstract

International audience; Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.

Published
2019
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11. An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

Author

Alessandro Raso, Alain Eychène, Antoine Forget, Michael D. Taylor, Morgane Morabito, Magalie Larcher, Franck Bourdeaut, Florence M.G. Cavalli, Liliana Mirabal-Ortega, Olivier Delattre, Chloe Foray, Abel Debalkew, François Doz, Julien Masliah-Planchon, Sophie Leboucher, Celio Pouponnot, Alexandra Garancher, Mamy Andrianteranagna, Stéphanie Puget, Sabine Druillennec, Olivier Ayrault, Department of Anatomy and Cell Biology [Montréal], McGill University, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), PSL Research University (PSL), Institut Curie, Université Paris Sud Orsay, Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Signalisation cellulaire et neurobiologie (SNC), McGill University = Université McGill [Montréal, Canada], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Institut Curie [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Cerebellum, Medicine (General), medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Apoptosis, Smad2 Protein, QH426-470, 0302 clinical medicine, Transforming Growth Factor beta, Phosphorylation, Receptor, Cancer, Inhibin-beta Subunits, activin, Articles, 3. Good health, Tumor Burden, Gene Expression Regulation, Neoplastic, Autocrine Communication, medicine.anatomical_structure, TGFbeta, Quinolines, Molecular Medicine, Female, Signal Transduction, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, medulloblastoma, Article, TGFbeta Subject Category Cancer, Transforming Growth Factor beta1, 03 medical and health sciences, R5-920, Transforming Growth Factor beta3, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cell Line, Tumor, medicine, Genetics, Galunisertib, Animals, Humans, Smad3 Protein, Autocrine signalling, Cerebellar Neoplasms, Cell Proliferation, Medulloblastoma, Chemotherapy, business.industry, Mechanism (biology), Membrane Proteins, medicine.disease, Xenograft Model Antitumor Assays, Radiation therapy, 030104 developmental biology, Cancer research, Pyrazoles, business, 030217 neurology & neurosurgery, Smad2, Smad3
Abstract

International audience; Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFb/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFb/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

Published
2019
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12. SHH medulloblastoma in a young adult with a TCF4 germline pathogenic variation

Author

Lydie Burglen, Olivier Ayrault, Irina Giurgea, Maud Blanluet, Franck Bielle, François Doz, David Gentien, Audrey Rapinat, Julien Masliah-Planchon, Olivier Delattre, Badreddine Mohand Oumoussa, Diane Doummar, Gaëlle Pierron, Christine Bourneix, Stéphane Clemenceau, Elodie Girard, Franck Bourdeaut, Celio Pouponnot, Mamy Andrianteranagna, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), École supérieure du professorat et de l'éducation - Académie de Grenoble (ESPE Grenoble), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Grenoble Alpes (UGA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurogénétique moléculaire, CHU Trousseau [APHP], Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Signalisation cellulaire et neurobiologie (SNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de recherche translationnelle, Institut Curie, Service de Génétique Oncologique, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Grenoble Alpes - École supérieure du professorat et de l'éducation - Académie de Grenoble (UGA ESPE Grenoble), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], and Département de Recherche Translationnelle

Subjects
Medulloblastoma, 0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, TCF4, Biology, medicine.disease, Germline, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Variation (linguistics), medicine, Neurology (clinical), Young adult, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2019
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13. Corrigendum to: Molecular subgrouping of atypical teratoid/rhabdoid tumors—a reinvestigation and current consensus

Author

Yura Grabovska, Marcel Kool, Martin Hasselblatt, Ben Ho, Daniel Williamson, Annie Huang, Mamy Andrianteranagna, Fu Pan Yao, Franck Bourdeaut, Pascal Johann, and Michael C. Frühwald

Subjects
0303 health sciences, Cancer Research, Pathology, medicine.medical_specialty, business.industry, Rhabdoid tumors, 03 medical and health sciences, 0302 clinical medicine, Oncology, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, 030304 developmental biology
Published
2020
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14. Abstract B68: Spatial and temporal conditions for Smarcb1 deletion determines mouse AT/RT (atypical teratoid/rhabdoid tumor) subtype

Author

Olivier Delattre, Amaury Leruste, Pascale Varlet, Volodia Dangouloff-Ros, Franck Bourdeaut, Mamy Andrianteranagna, Gaëlle Pierron, Paul Fréneaux, Céline Chauvin, Kevin Beccaria, Arnault Tauziède-Espariat, Christelle Dufour, Maria Jesus-Lobon-Iglesias, Joshua J. Waterfall, Didier Surdez, Christine Bourneix, Zhi-Yan Han, and Julien Masliah-Planchon

Subjects
Cancer Research, Cancer, Biology, medicine.disease, Pediatric cancer, Phenotype, Neural stem cell, Oncology, Conditional gene knockout, Atypical teratoid rhabdoid tumor, medicine, Cancer research, Progenitor cell, SMARCB1
Abstract

The cell(s) of origin of AT/RTs remain(s) unknown. We previously developed a mouse model consisting of tamoxifen inducible system in a Smarcb1Flox/Flox;Rosa26-CreERT2 background. We obtained two molecular subgroups of intracranial tumors, one with neuronal and the other with non-neuronal features, consistent with the diversity observed in human AT/RTs. To investigate the potential cell(s) of origin of these various AT/RTs, we first explored whether different time points of Smarcb1 inactivation correlated with anatomic location and/or molecular subgroups. We observed that the neuronal group, primarily developing from the subventricular zone and the spinal cord, was almost exclusively obtained with the earliest inactivation time points (E6-E7). In contrast, the non-neuronal group emerged upon Smarcb1 inactivation at any time point (E6-E10) and showed intracranial but extra-parenchymal/meningeal origins. High-resolution analysis of anatomic distribution of 55 human AT/RT and molecular subgroups is in progress. In order to more specifically identify the cell(s) of origin for the neuronal group, we next generated developmental stage-specific conditional knockout mice carrying Smarcb1 inactivation by restricting Cre expression with promoters characteristic for various neural stem cells/progenitors. While Smarcb1Flox/Flox;Atoh1CreERT2 showed ataxia but failed to give rise to any tumor at any embryonal time point, Smarcb1Flox/Flox;Ascl1CreERT2 did not show any phenotype. Targeting Nestin-expressing cells led to tumors with morphologic rhabdoid features; these tumors again showed molecular diversity as observed in human AT/RTs. In conclusion, we show that deletion of Smarcb1 determines mouse AT/RT subtypes depending on spatial and temporal factors. Our new mouse models not only give insight into the cell(s) of origin, but also provide interesting preclinical models of AT/RTs. Citation Format: Zhi-Yan Han, Mamy Andrianteranagna, Maria Jesus-Lobon-Iglesias, Arnault Tauziède-Espariat, Kevin Beccaria, Paul Fréneaux, Joshua J. Waterfall, Julien Masliah-Planchon, Christine Bourneix, Gaelle Pierron, Amaury Leruste, Céline Chauvin, Didier Surdez, Pascale Varlet, Christelle Dufour, Olivier Delattre, Volodia Dangouloff-Ros, Franck Bourdeaut. Spatial and temporal conditions for Smarcb1 deletion determines mouse AT/RT (atypical teratoid/rhabdoid tumor) subtype [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B68.

Published
2020
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15. Characterization of the grapevine Shaker K

Author

Manuel, Nieves-Cordones, Mamy, Andrianteranagna, Teresa, Cuéllar, Isabelle, Chérel, Rémy, Gibrat, Martin, Boeglin, Bertrand, Moreau, Nadine, Paris, Jean-Luc, Verdeil, SabineDagmar, Zimmermann, and Isabelle, Gaillard

Subjects
Potassium Channels, Xenopus, Flowers, Hydrogen-Ion Concentration, Droughts, Gene Expression Regulation, Plant, Stress, Physiological, Fruit, Oocytes, Potassium, Animals, Pulvinus, Vitis, RNA, Messenger, Plant Proteins
Abstract

In grapevine, climate changes lead to increased berry potassium (K

Published
2018

16. ATRT-35. SMARCB1-DEFICIENT TUMORS ACTIVATE BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES AND ARE SUSCEPTIBLE TO CHECKPOINT BLOCKADE AND TLR3 ACTIVATION

Author

Jimena Tosello, Christine Sedlick, Pamela Caudana, Louise Galmiche-Rolland, Arnault Tauziède-Espariat, Eliane Piaggio, Rodrigo Nalio Ramos, Joshua J. Waterfall, Solene Brohard, Mamy Andrianteranagna, Philippe Benaroch, Julien Masliah-Planchon, Olivier Delattre, Franck Bourdeaut, Aurore Coulomb, Céline Chauvin, Dominique Ranchère, Jovan Nikolic, Amaury Leruste, and Zhi-Yan Han

Subjects
Cancer Research, medicine.diagnostic_test, Interferon type II, Microglia, medicine.medical_treatment, T lymphocyte, Immunotherapy, Biology, Blockade, Flow cytometry, Abstracts, Immune system, medicine.anatomical_structure, Oncology, TLR3, medicine, Cancer research, Neurology (clinical), medicine.drug
Abstract

In order to evaluate the immune infiltrate of AT/RT, we conducted a combined immunohistochemical, multiparametric flow cytometry and transcriptomic analysis of a series of 49 human AT/RT. This revealed substantial heterogeneity, with some subgroups of AT/RT showing a prominent immune infiltrate. In details, our analyses indicated that: i) myeloid cells were the most abundant immune population, including both microglial cells and non-resident pro-tumoral M2-polarized macrophages, ii) tumor-infiltrating lymphocytes consisted in equal proportions of CD4+ and CD8+ T cells with few regulatory T cells, and iii) immune modulatory molecules PD-L1 and TIM-3 were expressed at high levels. Intratumoral cytolytic activity of CD8+ T cells highly correlated with both interferon gamma and alpha signatures, confirming the involvement of both adaptive and innate immune cells in the anti-tumor response. A genetically engineered mouse model of AT/RT recently established in our laboratory recapitulates many of these traits, including important infiltration by both lymphoid and myeloid cells sharing similar phenotypic characteristics. Using this model, we showed that blockade of the PD-1/PD-L1 pathway significantly impaired tumor growth and induced memory against a second engraftment, confirming an anti-tumoral T cell memory response. Combination with TIM-3 blockade showed synergistic effects. Additionally, targeting the myeloid infiltrate by TLR3 activation with poly(I:C) induced a potent anti-tumor effect which, combined with PD-1 blockade, led to complete tumor regression in over 85% of treated mice. In conclusion, we demonstrate that immune infiltration is a recurrent property of AT/RT and that immunotherapy, particularly combination regimens, have promising therapeutic potential.

Published
2018

17. ATRT-10. SPATIO-TEMPORAL DELETION OF SMARCB1 DETERMINES MOUSE AT/RT SUBTYPES

Author

Paul Fréneaux, Olivier Delattre, Christine Bourneix, Gaëlle Pierron, Mamy Andrianteranagna, Franck Bourdeaut, Céline Chauvin, Zhi-Yan Han, Amaury Leruste, Pascale Varlet, Julien Masliah-Planchon, Arnault Tauziède-Espariat, and Didier Surdez

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Ataxia, SMARCB1 Protein, Biology, Spinal cord, Neural stem cell, Abstracts, medicine.anatomical_structure, Oncology, Parenchyma, medicine, Neurology (clinical), medicine.symptom, SMARCB1, Tamoxifen, medicine.drug
Abstract

The cell(s) of origin of AT/RTs remains unclear. We previously developed a mouse model consisting in tamoxifen inducible system in a Smarcb1(Flox/Flox);Rosa26-Cre(ERT2) background. We obtained two subgroups of intracranial tumors, one with neuronal and the other with non-neuronal features, in keeping with the diversity observed in human AT/RTs. To investigate the potential cell(s) of origin of those various AT/RTs, we first endeavored to specify whether different time points of Smarcb1 inactivation correlated with specific anatomic location and/or molecular subgroups. Thereby, we identified that the neuronal group, mostly developing from the sub-ventricular zone and the spinal cord, was almost exclusively obtained with the earliest inactivation time point(E6-E7). In contrary, the non-neuronal group emerged after Smarcb1 inactivation at any time point(E6-E10), and showed intracranial but extra-parenchyma/meningeal origins. In order to more specifically identify the cell(s) of origin for the neuronal group, we next generated developmental stage-specific conditional knockout mice carrying Smarcb1 inactivation by restricting Cre expression upon promoters characteristic for various neural stem cells/progenitors. While Smarcb1(Flox/Flox);Atoh1Cre(ERT2) showed ataxia but failed to give rise to any tumor whatever the embryonal time point, targeting Nestin-expressing cells led to tumors with morphological rhabdoid features; these again showed some molecular diversity as observed in human AT/RTs. The study of the impact of Smarcb1 inactivation in other promoter-restricted backgrounds is ongoing. In conclusion, we show that spatio-temporal deletion of Smarcb1 determines mouse AT/RT subtypes. Our new mouse models not only give insight on the cell(s) of origin, but also provide interesting preclinical models.

Published
2018

18. High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors

Author

Aurianne Lescure, Laetitia Maillot, Wilfrid Richer, Elodie Anthony, Sergio Roman-Roman, Céline Chauvin, Marie-Ming Aynaud, Franck Bourdeaut, Arnault Tauziède-Espariat, Amaury Leruste, Olivier Delattre, Sakina Zaidi, Didier Surdez, Mylène Bohec, Sylvain Baulande, Elaine Del Nery, Mamy Andrianteranagna, Stefano Cairo, Zhi-Yan Han, and Julien Masliah-Planchon

Subjects
0301 basic medicine, Drug, Indazoles, Receptor, Platelet-Derived Growth Factor alpha, Combination therapy, media_common.quotation_subject, Antineoplastic Agents, Apoptosis, General Biochemistry, Genetics and Molecular Biology, Receptor tyrosine kinase, Pazopanib, Receptor, Platelet-Derived Growth Factor beta, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, Medicine, Humans, SMARCB1, lcsh:QH301-705.5, Protein Kinase Inhibitors, Rhabdoid Tumor, media_common, Sulfonamides, biology, business.industry, Rhabdoid tumors, SMARCB1 Protein, Endoplasmic Reticulum Stress, High-Throughput Screening Assays, Clinical trial, Quaternary Ammonium Compounds, 030104 developmental biology, Pyrimidines, lcsh:Biology (General), 030220 oncology & carcinogenesis, Cancer research, biology.protein, business, medicine.drug
Abstract

Summary: Rhabdoid tumors (RTs) are aggressive tumors of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRα/β and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs. : Rhabdoid tumors (RTs) are aggressive pediatric tumors characterized by SMARCB1 inactivation. Chauvin et al. identify two SMARCB1-dependent targeted therapies for RT: pazopanib, which inhibits PDGFR and FGFR2, and the potassium channel inhibitor clofilium tosylate, which induces endoplasmic reticulum stress. Combining both drugs induces cell apoptosis and reduces PDX tumor growth. Keywords: rhabdoid tumors, SMARCB1, pazopanib, clofilium tosylate, high-throughput drug screening, tyrosine kinase inhibitors

Published
2017

19. Potassium transport in developing fleshy fruits: the grapevine inward K(+) channel VvK1.2 is activated by CIPK-CBL complexes and induced in ripening berry flesh cells

Author

Isabelle Gaillard, Hervé Sentenac, Jean-Luc Verdeil, Sabine Zimmermann, François Pascaud, Farrukh Azeem, Mamy Andrianteranagna, Teresa Cuéllar, Sciences Pour l'Oenologie (SPO), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), 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)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), 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), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), 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)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut National de la Recherche Agronomique, Higher Education Commission of Pakistan, Conabex Commission of Madagascar, ANR-05-GPLA-0024,MUSTGRAPE,Vers une amélioration de la qualité du raisin et de la vendange: identification et caractérisation de transporteurs impliqués dans la charge en K+ de la baie de raisin(2005), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD [Nouvelle-Calédonie])-Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), and Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)

Subjects
0106 biological sciences, [SDV]Life Sciences [q-bio], grape berry flesh cells, Plant Science, Berry, 01 natural sciences, Veraison, Gene Expression Regulation, Plant, Arabidopsis, Vitis, Cloning, Molecular, Phylogeny, Plant Proteins, 0303 health sciences, biology, Ripening, Potassium channel, Physiologie végétale, Cell biology, Droughts, Biochemistry, K+ uptake, Female, Stress dû à la sécheresse, F60 - Physiologie et biochimie végétale, Molecular Sequence Data, Protein Serine-Threonine Kinases, 03 medical and health sciences, Genetics, Animals, CIPK-CBL network, Potassium Channels, Inwardly Rectifying, Ion transporter, 030304 developmental biology, Ion Transport, Arabidopsis Proteins, Calcium-Binding Proteins, Cell Biology, biology.organism_classification, Vascular bundle, expression pattern, Vitis vinifera, Fruit, Oocytes, Potassium, Shaker Superfamily of Potassium Channels, in situ hybridization, Phloem, Shaker K+ channel, 010606 plant biology & botany
Abstract

International audience; The grape berry provides a model for investigating the physiology of non-climacteric fruits. Increased K(+) accumulation in the berry has a strong negative impact on fruit acidity (and quality). In maturing berries, we identified a K(+) channel from the Shaker family, VvK1.2, and two CBL-interacting protein kinase (CIPK)/calcineurin B-like calcium sensor (CBL) pairs, VvCIPK04-VvCBL01 and VvCIPK03-VvCBL02, that may control the activity of this channel. VvCBL01 and VvCIPK04 are homologues of Arabidopsis AtCBL1 and AtCIPK23, respectively, which form a complex that controls the activity of the Shaker K(+) channel AKT1 in Arabidopsis roots. VvK1.2 remained electrically silent when expressed alone in Xenopus oocytes, but gave rise to K(+) currents when co-expressed with the pairs VvCIPK03-VvCBL02 or VvCIPK04-VvCBL01, the second pair inducing much larger currents than the first one. Other tested CIPK-CBL pairs expressed in maturing berries were found to be unable to activate VvK1.2. When activated by its CIPK-CBL partners, VvK1.2 acts as a voltage-gated inwardly rectifying K(+) channel that is activated at voltages more negative than -100 mV and is stimulated upon external acidification. This channel is specifically expressed in the berry, where it displays a very strong induction at veraison (the inception of ripening) in flesh cells, phloem tissues and perivascular cells surrounding vascular bundles. Its expression in these tissues is further greatly increased upon mild drought stress. VvK1.2 is thus likely to mediate rapid K(+) transport in the berry and to contribute to the extensive re-organization of the translocation pathways and transport mechanisms that occurs at veraison.

Published
2010
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