32 results on '"David Herrero-Martin"'
Search Results
2. Supplementary Table S2 from PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma
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Beat W. Schäfer, Ewa Koscielniak, Bernd Blank, Paolo Nanni, Peter Bode, Marco Wachtel, Maria E. Gierisch, Dominik Laubscher, Regina Hecker, David Herrero-Martin, Laura A. Lopez-Garcia, and Verena Thalhammer
- Abstract
Supplementary Table S2. Small-molecule library.
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- 2023
3. Data from PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma
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Beat W. Schäfer, Ewa Koscielniak, Bernd Blank, Paolo Nanni, Peter Bode, Marco Wachtel, Maria E. Gierisch, Dominik Laubscher, Regina Hecker, David Herrero-Martin, Laura A. Lopez-Garcia, and Verena Thalhammer
- Abstract
Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503, leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as a target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1–mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free survival and overall survival. Taken together, these preclinical studies validate the PLK1–PAX3-FOXO1 axis as a rational target to treat aRMS. Cancer Res; 75(1); 98–110. ©2014 AACR.
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- 2023
4. Supplementary Figure Legends from PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma
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Beat W. Schäfer, Ewa Koscielniak, Bernd Blank, Paolo Nanni, Peter Bode, Marco Wachtel, Maria E. Gierisch, Dominik Laubscher, Regina Hecker, David Herrero-Martin, Laura A. Lopez-Garcia, and Verena Thalhammer
- Abstract
Supplementary Figure Legends. Legend for Supplementary Figures S1-S7.
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- 2023
5. Supplementary Materials and Methods from PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma
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Beat W. Schäfer, Ewa Koscielniak, Bernd Blank, Paolo Nanni, Peter Bode, Marco Wachtel, Maria E. Gierisch, Dominik Laubscher, Regina Hecker, David Herrero-Martin, Laura A. Lopez-Garcia, and Verena Thalhammer
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Supplementary Materials and Methods. Description of additional methods and procedures used in the study.
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- 2023
6. LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity
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Olga Almacellas-Rabaiget, Santiago Rello-Varona, Paola Monaco, O.M. Tirado, Juan Huertas-Martinez, Susana Maqueda-Marcos, Silvia Garcia-Monclús, Isabel Fabra-Heredia, Roser López-Alemany, Enrique de Álava, Mariona Chicón-Bosch, David Herrero-Martin, Paloma H. Giangrande, Fundación Alba Pérez, Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya, and Fundación Científica Asociación Española Contra el Cáncer
- Subjects
0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,Carcinogenesis ,Cell ,Mice, Nude ,Vimentin ,Lysyl oxidase ,Apoptosis ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Cell migration ,Rhabdomyosarcoma ,Rhabdomyosarcoma, Alveolar ,Cell Proliferation ,biology ,LOXL2 ,Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,Cell invasion ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Alveolar rhabdomyosarcoma ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Biocatalysis ,Disease Progression ,Female ,Amino Acid Oxidoreductases - Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. Patients with the most aggressive histological variant have an unfavorable prognosis due to a high metastasis incidence. Lysyl oxidase-like 2 (LOXL2) is a lysyl oxidase, member of a family of extracellular matrix (ECM) crosslinking enzymes that recently have emerged as important regulators of tumor progression and metastasis. We report that LOXL2 is overexpressed in RMS, suggesting a potential role for LOXL2 in RMS oncogenic progression. Consistently, transient and stable LOXL2 knockdown decreased cell migratory and invasive capabilities in two ARMS cell lines. Furthermore, introduction of LOXL2 in RMS non-expressing cells using wild type or mutated (catalytically inactive) constructs resulted in increased cell migration, cell invasion and number and incidence of spontaneous lung metastasis in vivo, independently of its catalytic activity. To further study the molecular mechanism associated with LOXL2 expression, a pull-down assay on LOXL2-transfected cells was performed and analyzed by mass spectrometry. The intermediated filament protein vimentin was validated as a LOXL2-interactor. Thus, our results suggest an oncogenic role of LOXL2 in RMS by regulating cytoskeleton dynamics and cell motility capabilities., OMT: Fundación Alba Pérez lucha contra el cáncer infantil. Instituto de Salud Carlos III (CES12/021; PI11/00038; PI15/00035; AC14/00026) and EU's Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa/A way to achieve Europe.” CERCA Program/Generalitat de Catalunya (2017SGR332). OA-R, DH-M: Fundación Científica de la AECC. SG-M, SR-V: Fundación Alba Pérez lucha contra el cáncer infantil. PM: European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement ITN: 766214 – ESR 4.
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- 2020
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7. EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma
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Santi Rello-Varona, Olga Almacellas-Rabaiget, Roser López-Alemany, Jaume Mora, Piedad Alba-Pavón, Enrique de Álava, Juan Huertas-Martinez, Lourdes Hontecillas-Prieto, Silvia Garcia-Monclús, David Herrero-Martin, Laura Lagares-Tena, Paloma H. Giangrande, and O.M. Tirado
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0301 basic medicine ,Cancer Research ,Gene knockdown ,biology ,Angiogenesis ,Cell migration ,medicine.disease ,EPH receptor A2 ,Receptor tyrosine kinase ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,Oncology ,medicine ,biology.protein ,Cancer research ,Gene silencing ,Sarcoma - Abstract
Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in Ewing sarcoma (ES) cells via ligand-dependent signaling. Now we wanted to explore EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2S897 ), as it has been linked to metastasis in several malignancies. By reverse genetic engineering we explored the phenotypic changes after EphA2 removal or reintroduction. Gene expression microarray was used to identify key players in EphA2 signaling. Mice were employed to reproduce metastatic processes from orthotopically implanted engineered cells. We established a correlation between ES cells aggressiveness and p-EphA2S897 . Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a non-phosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing. Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.
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- 2018
8. Caveolin-1 promotes Ewing sarcoma metastasis regulating MMP-9 expression through MAPK/ERK pathway
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Roser López-Alemany, Oscar M. Tirado, Juan Huertas-Martinez, Silvia Garcia-Monclús, Carlos Rodriguez-Galindo, Olga Almacellas-Rabaiget, Santiago Rello-Varona, Miguel Sáinz-Jaspeado, David Herrero-Martin, Laura Lagares-Tena, and Silvia Mateo-Lozano
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0301 basic medicine ,MAPK/ERK pathway ,Pathology ,Oncogene Proteins, Fusion ,Caveolin 1 ,Metastasis ,Mice ,0302 clinical medicine ,IQGAP1 ,Cell Movement ,Medicine ,Neoplasm Metastasis ,Phosphorylation ,Mice, Inbred BALB C ,Ribosomal Protein S6 ,Kinase ,Soft tissue sarcoma ,Extracellular Matrix ,Matrix Metalloproteinase 9 ,Oncology ,ras GTPase-Activating Proteins ,030220 oncology & carcinogenesis ,FLI1 ,Female ,Sarcoma ,Research Paper ,caveolin-1 ,medicine.medical_specialty ,MAP Kinase Signaling System ,Mice, Nude ,Sarcoma, Ewing ,Ribosomal Protein S6 Kinases, 90-kDa ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,metastasis ,Neoplasm Invasiveness ,Gene Silencing ,mapk ,Proto-Oncogene Protein c-fli-1 ,business.industry ,medicine.disease ,030104 developmental biology ,mmp9 ,Cancer research ,RNA-Binding Protein EWS ,business ,Ewing sarcoma - Abstract
// Laura Lagares-Tena 1 , Silvia Garcia-Monclus 1 , Roser Lopez-Alemany 1 , Olga Almacellas-Rabaiget 1 , Juan Huertas-Martinez 1 , Miguel Sainz-Jaspeado 1 , Silvia Mateo-Lozano 2 , Carlos Rodriguez-Galindo 3 , Santiago Rello-Varona 1 , David Herrero-Martin 1 , Oscar M. Tirado 1 1 Sarcoma Research Group, Institut d’Investigacio Biomedica de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain 2 Developmental Tumor Biology Laboratory, Hospital Sant Joan de Deu, Barcelona, Spain 3 Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA Correspondence to: Oscar M. Tirado, email: omartinez@idibell.cat Keywords: caveolin-1, Ewing sarcoma, metastasis, mmp9, mapk Received: December 22, 2015 Accepted: July 18, 2016 Published: July 28, 2016 ABSTRACT Ewing sarcoma (ES) is a bone and soft tissue sarcoma affecting mostly children and young adults. Caveolin-1 (CAV1) is a well-known target of EWS/FLI1, the main driver of ES, with an oncogenic role in ES. We have previously described how CAV1 is able to induce metastasis in ES via matrix metalloproteinase-9 (MMP-9). In the present study we showed how CAV1 silencing in ES reduced MEK1/2 and ERK1/2 phosphorylation. Accordingly, chemical inhibition of MEK1/2 resulted in reduction in MMP-9 expression and activity that correlated with reduced migration and invasion. IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) silencing reduced MEK1/2 and ERK1/2 phosphorylation and MMP-9 expression. Furthermore, IQGAP1 silenced cells showed a marked decrease in their migratory and invasive capacity. We demonstrated that CAV1 and IQGAP1 localize in close proximity at the cellular edge, thus IQGAP1 could be the connecting node between CAV1 and MEK/ERK in ES metastatic phenotype. Analysis of the phosphorylation profile of CAV1-silenced cells showed a decrease of p-ribosomal protein S6 (RPS6). RPS6 can be phosphorylated by p90 ribosomal S6 kinases (RSK) proteins. CAV1-silenced cells showed reduced levels of p-RSK1 and treatment with U0126 provoked the same effect. Despite not affecting ERK1/2 and RPS6 phosphorylation status neither MMP-9 expression nor activity, RSK1 silencing resulted in a reduced migratory and invasive capacity in vitro and reduced incidence of metastases in vivo in a novel orthotopic model. The present work provides new insights into CAV1-driven metastatic process in ES unveiling novel key nodes.
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- 2016
9. '(Not) All (Dead) Things Share the Same Breath': Identification of Cell Death Mechanisms in Anticancer Therapy
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Oscar M. Tirado, Cristina Muñoz-Pinedo, Roser López-Alemany, David Herrero-Martin, and Santiago Rello-Varona
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Cancer Research ,Programmed cell death ,medicine.anatomical_structure ,Oncology ,Cell ,medicine ,Cancer ,Identification (biology) ,Cancer cell lines ,Biology ,Bioinformatics ,medicine.disease ,Frequent use - Abstract
During the last decades, the knowledge of cell death mechanisms involved in anticancer therapy has grown exponentially. However, in many studies, cell death is still described in an incomplete manner. The frequent use of indirect proliferation assays, unspecific probes, or bulk analyses leads too often to misunderstandings regarding cell death events. There is a trend to focus on molecular or genetic regulations of cell demise without a proper characterization of the phenotype that is the object of this study. Sometimes, cancer researchers can feel overwhelmed or confused when faced with such a corpus of detailed insights, nomenclature rules, and debates about the accuracy of a particular probe or assay. On the basis of the information available, we propose a simple guide to distinguish forms of cell death in experimental settings using cancer cell lines. Cancer Res; 75(6); 913–7. ©2015 AACR.
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- 2015
10. PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma
- Author
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Regina Hecker, Ewa Koscielniak, Peter K. Bode, Maria E. Gierisch, David Herrero-Martin, Bernd Blank, Laura A. Lopez-Garcia, Marco Wachtel, Verena Thalhammer, Dominik Laubscher, Paolo Nanni, Beat W. Schäfer, University of Zurich, and Schäfer, Beat W
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Male ,Cancer Research ,Oncogene Proteins, Fusion ,Druggability ,610 Medicine & health ,Cell Cycle Proteins ,Mice, SCID ,Protein Serine-Threonine Kinases ,Transfection ,PLK1 ,Small Molecule Libraries ,Mice ,Mice, Inbred NOD ,10049 Institute of Pathology and Molecular Pathology ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Paired Box Transcription Factors ,1306 Cancer Research ,Kinome ,Phosphorylation ,RNA, Small Interfering ,Rhabdomyosarcoma ,Transcription factor ,Rhabdomyosarcoma, Alveolar ,business.industry ,Kinase ,medicine.disease ,3. Good health ,HEK293 Cells ,Oncology ,10036 Medical Clinic ,10032 Clinic for Oncology and Hematology ,Cancer research ,Alveolar rhabdomyosarcoma ,Heterografts ,2730 Oncology ,Female ,Protein stabilization ,business - Abstract
Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503, leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as a target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1–mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free survival and overall survival. Taken together, these preclinical studies validate the PLK1–PAX3-FOXO1 axis as a rational target to treat aRMS. Cancer Res; 75(1); 98–110. ©2014 AACR.
- Published
- 2015
11. DNA methylation profiling identifies PTRF/Cavin-1 as a novel tumor suppressor in Ewing sarcoma when co-expressed with caveolin-1
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Jaume Mora, Enrique de Álava, Soledad Gallego, Paloma H. Giangrande, Xavier Garcia del Muro, Oscar M. Tirado, Manel Esteller, Silvia Garcia-Monclús, Laura Lagares-Tena, Xavier Sanjuan, Miguel Sáinz-Jaspeado, David Herrero-Martin, Josep Roma, Lourdes Hontecillas-Prieto, Ana Sastre, Dave Monk, Olga Almacellas-Rabaiget, Juan Huertas-Martinez, Santiago Rello-Varona, Franck Court, M A Peinado, Raquel Buj, Sebastian Moran, Javier Alonso, Roser López-Alemany, and Daniel Azorín
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0301 basic medicine ,Cancer Research ,Caveolin 1 ,Apoptosis ,Kaplan-Meier Estimate ,Epigenesis, Genetic ,Caveolae ,Genes, Tumor Suppressor ,Phosphorylation ,DNA methylation ,RNA-Binding Proteins ,Proto-Oncogene Proteins c-mdm2 ,Methylation ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Oncology ,CpG site ,PTRF ,Mdm2 ,Sarcoma ,Signal Transduction ,Mice, Nude ,Bone Neoplasms ,Sarcoma, Ewing ,Biology ,Transfection ,03 medical and health sciences ,Cavin-1 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epigenetics ,Cell Proliferation ,Gene Expression Profiling ,DNA Methylation ,medicine.disease ,Molecular biology ,030104 developmental biology ,Spain ,Cancer research ,biology.protein ,Ewing sarcoma ,Tumor Suppressor Protein p53 - Abstract
Epigenetic modifications have been shown to be important in developmental tumors as Ewing sarcoma. We profiled the DNA methylation status of 15 primary tumors, 7 cell lines, 10 healthy tissues and 4 human mesenchymal stem cells lines samples using the Infinium Human Methylation 450K. Differential methylation analysis between Ewing sarcoma and reference samples revealed 1166 hypermethylated and 864 hypomethylated CpG sites (Bonferroni p < 0.05, delta-beta-value with absolute difference of >0.20) corresponding to 392 and 470 genes respectively. Gene Ontology analysis of genes differentially methylated in Ewing sarcoma samples showed a significant enrichment of developmental genes. Membrane and cell signal genes were also enriched, among those, 11 were related to caveola formation. We identified differential hypermethylation of CpGs located in the body and S-Shore of the PTRF gene in Ewing sarcoma that correlated with its repressed transcriptional state. Reintroduction of PTRF/Cavin-1 in Ewing sarcoma cells revealed a role of this protein as a tumor suppressor. Restoration of caveolae in the membrane of Ewing sarcoma cells, by exogenously reintroducing PTRF, disrupts the MDM2/p53 complex, which consequently results in the activation of p53 and the induction of apoptosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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- 2017
12. A novel orthotopic mouse model in sarcomas
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Santi Rello-Varona, O Almacellas Rabaiget, Juan Huertas-Martinez, David Herrero-Martin, O.M. Tirado, R. López-Alemany, Silvia Garcia-Monclús, and Laura Lagares-Tena
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medicine.medical_specialty ,business.industry ,Pediatrics, Perinatology and Child Health ,Cancer research ,Medicine ,business ,Surgery - Published
- 2016
13. Epigenetic profiling identifies MIR10A-5 p as a putative tumor suppresor in Ewing sarcoma and rhabdomyosarcoma
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Miguel Sáinz-Jaspeado, O.M. Tirado, Franck Court, E de Álava, Sebastian Moran, M A Peinado, Santi Rello-Varona, Raquel Buj, Juan Huertas-Martinez, David Herrero Martin, Jaume Mora, Silvia Garcia-Monclús, Manel Esteller, and Javier Alonso
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Pathology ,medicine.medical_specialty ,Pediatrics, Perinatology and Child Health ,medicine ,Profiling (information science) ,Sarcoma ,Epigenetics ,Biology ,medicine.disease ,Rhabdomyosarcoma - Published
- 2016
14. TThe ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24–25, 2015. Workshop Report
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Ornella Gonzato, Marie-cecile Ledeley, Emmy D.G. Fleuren, Hans Gelderblom, Marta Fiocco, Winette T. A. van der Graaf, Joachim Gerß, David Thomas, Jenny Potratz, Stefanie Hecker-Nolting, Craig Gerrand, Heinrich Kovar, Franck Tirode, Anne-Marie Cleton-Jansen, Piero Picci, Bernadette Brennan, Ola Myklebost, Javier Martin Broto, Judith V.M.G. Bovée, Michaela Nathrath, Piotr Rutkowski, Oscar M. Tirado, Aurélie Dutour, Nathalie Gaspar, Katia Scotlandi, Jeremy Whelan, Laurence Brugières, B. Hassan, Lindsey Bennister, Leo Kager, Gilles Vassal, Martin G. McCabe, Gunther Richter, Stefan S. Bielack, Carlo Lancia, Christopher Copland, Ruth Ladenstein, Stephanie Klco-Brosius, Jakob K. Anninga, Françoise Rédini, David Herrero-Martin, Markus Metzler, Franca Fagioli, Denise Reinke, Uta Dirksen, Stefano Ferrari, Sandra J. Strauss, Department of Paediatrics [Vienna, Austria], Saint Anna Children's Hospital [Vienna, Austria]-Medizinische Universität Wien = Medical University of Vienna, Children’s Cancer Research Institute [Vienna, Austria], University College London Hospitals (UCLH), Universitätsklinikum Münster [Munster, Germany], University of Oxford [Oxford], Leids Universitair Medisch Centrum [Leiden, The Netherlands], Sarcoma Patients Euronet [London, UK], Sarcoma UK, Central Manchester University Hospitals [Manchester, U.K.], Hospital Universitario Virgen del Rocío [Sevilla], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), CELT [York, UK], University of York [York, UK], 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Regina Margherita University Children's Hospital [Turin, Italy], Istituto Ortopedico Rizzoli [Bologna, Italy], Radboud University Medical Centre [Nijmegen, The Netherlands], Newcastle upon Tyne Hospitals [Newcastle, UK], Institute of Cancer Research - ICR [London, U.K.], Klinikum Stuttgart-Olgahospital [Stuttgart, Germany], Molecular Oncology Laboratory [Barcelona, Spain] (Sarcoma Research Group), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL)-L’Hospitalet de Llobregat [Barcelona, Spain], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University of Manchester [Manchester], Universitätsklinikum Erlangen [Erlangen, Germany], Oslo University Hospital [Oslo], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Klinikum Kassel [Kassel, Germany], Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sarcoma Alliance through Research and Collaboration [Ann Arbor, USA], Maria Sklodowska-Curie Memorial Institute and Cancer Centre [Warsaw, Poland], Garvan Institute of Medical Research [Darlinghurst, Australia], Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], The research leading to these results and the information described in this article have received funding from ENCCA-WP7: The European Union’s Seventh Framework Programme (FP7/2007-2013) under the project ENCCA, Grant agreement HEALTH-F2-2011-261474. EuroSarc: EU project FP7-HEALTH-2011-two-stage, Project ID 278742 EUROSARC. EEC: European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant agreement no. 602856PROVABES: ERA-Net-TRANSCAN (01KT1310). PanCareLife: (602030-2) EU-FP7German Cancer Aid: DKH 108128. EURAMOS: The EURAMOS-group has received support from multiple funders (see Bielack et al., J Clin Oncol 33(20):2279-87, 2015)., European Project: 261474,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,ENCCA(2011), European Project: 278742,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,EUROSARC(2011), European Project: 602856,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,EEC(2013), European Project: 602030,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PANCARELIFE(2013), Medizinische Universität Wien = Medical University of Vienna-Saint Anna Children's Hospital [Vienne] = St Anna Kinderspital (St. Anna Children's Hospital), University of Oxford, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Garvan Institute of medical research, maurice, sandrine, EUROPEAN NETWORK for CANCER research in CHILDREN and ADOLESCENTS - ENCCA - - EC:FP7:HEALTH2011-01-01 - 2015-12-31 - 261474 - VALID, European Clinical trials in Rare Sarcomas within an integrated translational trial network - EUROSARC - - EC:FP7:HEALTH2011-12-01 - 2016-11-30 - 278742 - VALID, EURO EWING Consortium – International Clinical Trials to Improve Survival from Ewing Sarcoma - EEC - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602856 - VALID, and PanCare Studies in Fertility and Ototoxicity to Improve Quality of Life after Cancer during Childhood, Adolescence and Young Adulthood - PANCARELIFE - - EC:FP7:HEALTH2013-11-01 - 2018-10-31 - 602030 - VALID
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Pathology ,medicine.medical_specialty ,Translational research ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Meeting Report ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Bone Sarcoma ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Medisinske Fag: 700 [VDP] ,Medizinische Fakultät ,Next generation sequencing ,Bone sarcoma ,Journal Article ,medicine ,In patient ,Medical physics ,ddc:610 ,030212 general & internal medicine ,Ewing sarcoma ,Immunotherapy ,Osteosarcoma ,Pharmacogenomics ,Tumors ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Joint bone ,medicine.disease ,3. Good health ,Clinical trial ,Oncology ,030220 oncology & carcinogenesis ,Sarcoma ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 167540.pdf (Publisher’s version ) (Open Access) This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.
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- 2016
15. Factors Affecting EWS-FLI1 Activity in Ewing's Sarcoma
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Argyro Fourtouna, David Herrero-Martin, Stephan Niedan, Dave N. T. Aryee, Raphaela Schwentner, and Lucia T. Riedmann
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business.industry ,Ewing's sarcoma ,Chromosomal translocation ,Review Article ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Bioinformatics ,lcsh:RC254-282 ,Fusion protein ,Ews fli1 ,Oncology ,Cancer research ,Medicine ,Fatal disease ,Radiology, Nuclear Medicine and imaging ,Sarcoma ,business ,Transcription factor - Abstract
Ewing's sarcoma family tumors (ESFT) are characterized by specific chromosomal translocations, which give rise to EWS-ETS chimeric proteins. These aberrant transcription factors are the main pathogenic drivers of ESFT. Elucidation of the factors influencing EWS-ETS expression and/or activity will guide the development of novel therapeutic agents against this fatal disease.
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- 2011
16. Abstract B19: Tumor-suppressive activities associated to MIR10A-5p expression in developmental sarcomas
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Lee J. Helman, David Herrero-Martin, Juan Huertas-Martinez, Oscar M. Tirado, Olga Almacellas-Rabaiget, Santiago Rello-Varona, and Silvia Garcia-Monclús
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Transcriptome ,CRKL ,Cancer Research ,Oncology ,Cell growth ,DNA methylation ,Cancer research ,Gene silencing ,Cell migration ,Epigenetics ,Biology ,Clonogenic assay - Abstract
Ewing sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS) are pediatric sarcomas characterized by tumor-specific translocations. Besides acting as a direct modulator of transcription, fusion proteins appear to exert its oncogenic functions by epigenetic modifications on the transcriptome. Therefore, the identification of specific DNA methylation markers would be helpful for understanding their pathogenetic mechanism as well as for developing new therapeutic strategies. By using the Illumina Infinium HumanMethylation450 we have analyzed the methylome of ES and ARMS tumors and cell lines. ES and ARMS samples showed, among other epigenetic alterations, differential hypermethylation in the promoter of MIR10A-5p, thus suggesting an inhibition of its expression. Expression of MIR10A-5p is effectively low in ES and ARMS cell lines and patient samples and the treatment with the epigenetic modifier 5-aza restores its expression. MIR10A-5p stable overexpression in two ES (A673 and TC252) and two ARMS (Rh4 and RMS13) cell lines reduces proliferation, diminishes clonogenic growth, and decreases cellular migration. Cell death induced by MIR10A-5p reintroduction is only achieved in the p53wt ES cell line TC252. Proteomic profile of A673 MIR10A-5p cells is altered as assessed by iTRAQ. Protein kinase CRKL is one of the proteins downregulated due to MIR10A-5p reintroduction. Indeed, CRKL expression is also reduced in the other three MIR10A-5p stable overexpression models. Doxycycline-induced silencing of CRKL in ARMS cell line Rh30 provokes cell growth reduction in vitro and in vivo, G0/G1 arrest, and a decrease in the clonogenic capacity (Yeung CL et al., 2013). Interestingly, the migratory ability of Rh30 and A673 CRKL-silenced cells is also impaired. Thus, our results uncover MIR10A-5p as a putative tumor suppressor in ES and ARMS, suggesting a link between MIR10A-5p and CRKL. Further characterization of the oncogenic role of CRKL and the molecular mechanisms associated to MIR10A-5p tumor-suppressor activities in ES and ARMS is ongoing. Citation Format: David Herrero-Martin, Santiago Rello-Varona, Silvia Garcia-Monclus, Juan Huertas-Martinez, Olga Almacellas-Rabaiget, Lee J. Helman, Oscar M. Tirado. Tumor-suppressive activities associated to MIR10A-5p expression in developmental sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B19.
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- 2018
17. The Importance of Being Dead: Cell Death Mechanisms Assessment in Anti-Sarcoma Therapy
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Nuria Mulet-Margalef, Cristina Muñoz-Pinedo, Juan Huertas-Martinez, Santiago Rello-Varona, Oscar M. Tirado, Laura Lagares-Tena, Silvia Garcia-Monclús, Xavier Garcia del Muro, David Herrero-Martin, Roser López-Alemany, and Universitat de Barcelona
- Subjects
translocation-bearing sarcomas ,Cell death ,Cancer Research ,Programmed cell death ,Necrosis ,Context (language use) ,Apoptosis ,Review Article ,Biology ,Bioinformatics ,lcsh:RC254-282 ,medicine ,Autophagy ,Mitotic catastrophe ,mitotic catastrophe ,Mesenchymal stem cell ,Apoptosi ,Sarcoma ,medicine.disease ,Necrosi ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,autophagic cell death ,Mort cel·lular ,Cell Death Mechanisms ,medicine.symptom - Abstract
Cell death can occur through different mechanisms, defined by their nature and physiological implications. Correct assessment of cell death is crucial for cancer therapy success. Sarcomas are a large and diverse group of neoplasias from mesenchymal origin. Among cell death types, apoptosis is by far the most studied in sarcomas. Albeit very promising in other fields, regulated necrosis and other cell death circumstances (as so-called "autophagic cell death" or "mitotic catastrophe") have not been yet properly addressed in sarcomas. Cell death is usually quantified in sarcomas by unspecific assays and in most cases the precise sequence of events remains poorly characterized. In this review, our main objective is to put into context the most recent sarcoma cell death findings in the more general landscape of different cell death modalities.
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- 2015
18. The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
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María C. García-Macías, Cristina Teodosio, Miguel Aracil, Enrique de Álava, José Luis Ordóñez, Angel M. Carcaboso, Carlos M. Galmarini, Ana Teresa Amaral, Telmo Rodrigues, Monica Vila-Ubach, Laura San-Segundo, Oscar M. Tirado, Guillem Pascual-Pasto, David Herrero-Martin, Agustín Mayo-Iscar, Jaume Mora, Vicky Sevillano, Susana Fraile, Diego Herrero Alonso, Generalitat de Catalunya, Xarxa de Bancs de Tumors de Catalunya, Federación Española de Enfermedades Raras, Consejo Superior de Investigaciones Científicas (España), European Commission, Fundación Memoria de D. Samuel Solorzano Barruso, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, and Fundación CRIS contra el Cáncer
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DNA damage ,Poly ADP ribose polymerase ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Sarcoma ,Biology ,Poly (ADP-Ribose) Polymerase Inhibitor ,3. Good health ,Olaparib ,chemistry.chemical_compound ,PARP1 ,PARP inhibitor ,Oncology ,chemistry ,Immunology ,medicine ,Cancer research ,DNA fragmentation ,PDX models ,Trabectedin ,Ewing sarcoma ,medicine.drug - Abstract
Producción Científica, Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting., Ministerio de Economía y Competitividad (PI081828), Ministerio de Economía y Competitividad (RD06/0020/0059 ), Ministerio de Economía y Competitividad (RD12/0036/0017), Ministerio de Economía y Competitividad (PT13/0010/0056)
- Published
- 2015
19. Abstract 1929: A novel orthotopic mouse model in sarcomas
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David Herrero Martin, Oscar M. Tirado, Roser López Alemany, Laura Lagares Tena, Olga Almacellas Rabaiget, Silvia Garcia Monclús, Santiago Rello Varona, and Juan Huertas Martínez
- Subjects
Cancer Research ,biology ,business.industry ,Cancer ,Context (language use) ,EPH receptor A2 ,medicine.disease ,Receptor tyrosine kinase ,Metastasis ,Oncology ,biology.protein ,Cancer research ,medicine ,Sarcoma ,Clonogenic assay ,Rhabdomyosarcoma ,business - Abstract
Pediatric sarcomas are a heterogeneous group of bone and soft tissue malignancies affecting children and young adults. One of the most important prognostic factors of those diseases is the presence of metastasis at diagnosis. In that context, we have developed a novel orthotopic model which consists in injecting Ewing Sarcoma (ES) or Rhabdomyosarcoma (RMS) tumor cells at the gastrocnemius muscle of mice and extracting the tumor at a of 10 mm x 13 mm volume. After surgery, animals maintain a complete functional extremity and can live until lung metastasis detection (about 60 days post-injection). Moreover, we have validated the suitability of the model with an Ewing Sarcoma EphA2-low expression cell line. Epha2 is a tyrosine kinase receptor that has been found overexpressed in a wide variety of tumors and correlated with malignant phenotype. In this study we report that EphA2 receptor is phosphorylated at S897 in a panel of ES cell lines, which is related to the oncogenic properties of the receptor. Stable silencing of EphA2 in two different ES cell lines resulted in a decrease in the clonogenic, proliferation, migration and invasion capacity in vitro. Moreover, we performed an experimental metastasis assay, injecting tumor cells through the tail vain of mice and observed a reduction in the lung metastasis incidence in EphA2 silenced cells. We then used this new orthotopic metastasis model to validate the impairment in the invasion capacity of EphA2 silenced cells and confirm the decrease in lung metastasis incidence, indicating an oncogenic role for EphA2 in ES. This novel orthotopic metastasis model is a valuable tool both for the study of spontaneous metastasis and also for evaluating therapeutic index in the onset of metastasis, which can also be applied to the study of other pedriatric sarcomas. Citation Format: Silvia Garcia Monclús, Juan Huertas Martínez, Laura Lagares Tena, Santiago Rello Varona, Olga Almacellas Rabaiget, David Herrero Martin, Roser López Alemany, Oscar Martinez Tirado. A novel orthotopic mouse model in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1929. doi:10.1158/1538-7445.AM2017-1929
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- 2017
20. Correction: The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
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Carlos M. Galmarini, Agustín Mayo-Iscar, Enrique de Alava, Susana Fraile, María C. García-Macías, Jaume Mora, Guillem Pascual-Pasto, Miguel Aracil, Vicky Sevillano, Monica Vila-Ubach, Laura San-Segundo, Cristina Teodosio, Diego Herrero Alonso, David Herrero-Martin, Oscar M. Tirado, José Luis Ordóñez, Ana Teresa Amaral, Telmo Rodrigues, and Angel M. Carcaboso
- Subjects
Male ,Dioxoles ,Mice, SCID ,Sarcoma, Ewing ,Poly(ADP-ribose) Polymerase Inhibitors ,Piperazines ,Olaparib ,chemistry.chemical_compound ,Mice ,Random Allocation ,Mice, Inbred NOD ,Cell Line, Tumor ,Tetrahydroisoquinolines ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Child ,Trabectedin ,business.industry ,Correction ,Drug Synergism ,medicine.disease ,Xenograft Model Antitumor Assays ,PARP inhibitor ,Oncology ,chemistry ,Cancer research ,Phthalazines ,PDX models ,Sarcoma ,business ,Ewing sarcoma ,Research Paper ,medicine.drug ,DNA Damage - Abstract
Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
- Published
- 2017
21. Abstract 1918: The role of miR17-92 in the miRegulatory landscape of Ewing sarcoma
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Raphaela Schwentner, Heinrich Kovar, Maximilian Kauer, and David Herrero-Martin
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Cancer Research ,Gene knockdown ,Candidate gene ,Oncology ,microRNA ,Gene expression ,Ectopic expression ,SMAD ,Computational biology ,Transfection ,Biology ,Gene - Abstract
MicroRNAs (miRNA) serve to fine-tune gene expression and thus play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a given tissue still poses a significant problem since the presence of a seed sequence in the 3′UTR of an mRNA and its expression modulation upon forced ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in ES. Recently, we reported on the EWS-FLI1 microRNA (miRNA) signature based on knockdown experiments in ES cell lines and on differential expression in primary tumors versus mesenchymal stem cells. Comparison of both datasets revealed the miR17-92 cluster to be the top EWS-FLI1 activated miRNA, which is one of the most potent oncogenic miRNAs. The whole cluster is among the small number of miRNAs down-regulated upon knockdown of EWS-FLI1 in multiple ES cell lines. We now report the use of a combination of AGO2 pull-down experiments by PAR-CLIP - to enrich and sequence RISC-associated RNAs - and of RNAseq upon miRNA depletion by ectopic sponge expression to identify the targetome of miR17-92 in Ewing sarcoma (ES) cells We found a significant enrichment of PAR-CLIP hits for members of the miR-17-92 cluster in the 3′UTRs of genes up-regulated in response to mir-17-92 but not miR9 and 10b specific sponge expression. Among them, we consistently identified known (i.e. CTGF, MXD1, CYLD1) and a multitude of so far unknown targets of the oncomir-1 cluster in ES in three PAR-CLIP experiments. Interestingly, approximately a quarter of these genes annotate to the TGFB/BMP pathway, the majority mapping downstream of SMAD signaling. Gene reporter assays using 3’UTRs of select novel candidate genes showed enhancement of luciferase activity upon transfection of a sponge specific to miR-17-92 and 20a, but not to unrelated miR-9 and 10b. Site directed mutagenesis of seed sequences in these 3’UTR confirmed the direct regulation of these genes by miR17-92. Current research focuses on the functional validation of TGFB pathway modulation by miR17-92. This study provides a paradigmatic approach to the comprehensive definition of the targetome for a defined group of miRNAs under physiological conditions. This study was supported by the 7th framework program of the European Commission (FP7-259348, “ASSET”) and the Austrian Science Fund FWF (24708-B21) Citation Format: Raphaela Schwentner, Maximilian Kauer, David Herrero-Martin, Heinrich Kovar. The role of miR17-92 in the miRegulatory landscape of Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1918.
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- 2016
22. Abstract A40: Epigenomic profiling identifies NCRNAs as novel tumor suppressors in developmental tumors
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Jaume Mora, Javier Alonso, Manel Esteller, Santiago Rello-Varona, David Herrero-Martin, Oscar M. Tirado, Silvia Garcia-Monclús, Dave Monk, Sebastian Moran, Enrique de Alava, Franck Court, M A Peinado, Juan Huertas-Martinez, Raquel Buj, and Miguel Sáinz-Jaspeado
- Subjects
Cancer Research ,Oncology ,law ,Suppressor ,Profiling (information science) ,Computational biology ,Biology ,Bioinformatics ,Epigenomics ,law.invention - Abstract
Pediatric sarcomas represent a diverse group of rare bone and soft tissue malignancies. Although the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis. Besides of acting as a direct modulator of transcription, fusion proteins appear to exert its oncogenic functions by epigenetic modifications on the transcriptome. Aberrant DNA methylations are thought to be closely related to the development of cancer. Therefore, the identification of specific DNA methylation markers would be helpful for understanding the pathogenetic mechanism as well as for developing new therapeutic strategies. By using the Illumina Infinium HumanMethylation450, we analyze the methylome of Ewing Sarcoma (ES) and Rhabdomyosarcoma (RMS) tumors and cell lines as developmental tumors in comparison to a significant number of normal tissues and cells as a reference. Our results uncover one miRNA with tumor suppressive activities in both tumor entities. Molecular mechanisms associated to these activities are further explored. Citation Format: David Herrero-Martin, Franck Court, Santiago Rello-Varona, Miguel Sainz-Jaspeado, Raquel Buj, Sebastian Moran, Silvia Garcia-Monclus, Juan Huertas-Martinez, Jaume Mora, Miquel Angel Peinado, Javier Alonso, Enrique de Alava, Dave Monk, Manel Esteller, Oscar M. Tirado. Epigenomic profiling identifies NCRNAs as novel tumor suppressors in developmental tumors. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A40.
- Published
- 2016
23. The first European interdisciplinary ewing sarcoma research summit
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Jozef Ban, Enrique de Alava, Pierre Åman, Stephen L. Lessnick, Dave N. T. Aryee, Stefan Burdach, Udo Kontny, Stephan Niedan, Jeffrey A. Toretsky, Simone Fulda, Lee J. Helman, Raphaela Schwentner, Selena Ventura, Angelika Eggert, Françoise Rédini, Antonio Llombart-Bosch, Markus Metzler, Poul H. Sorensen, Beat W. Schäfer, Heinrich Kovar, Argyro Fourtouna, Katia Scotlandi, Gunther Richter, Sue A. Burchill, Uta Dirksen, Olivier Delattre, Richard Moriggl, Elizabeth R. Lawlor, David Herrero-Martin, Javier Alonso, Martin S. Staege, Lucia T. Riedmann, Pancras C.W. Hogendoorn, Franck Tirode, Ruth Ladenstein, Claudia Rossig, Jenny Potratz, Children’s Cancer Research Institute [Vienna, Austria], Department of Pediatrics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Sahlgrenska Academy at University of Gothenburg [Göteborg], Leeds Institute of Molecular Medicine, University of Leeds, Children’s Cancer Research Center and Department of Pediatrics [Munich, Germany], Technical University and Comprehensive Cancer Center Munich - CCCM [Germany]-Klinikum rechts der Isar [Munich, Germany], University Hospital of Salamanca, 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), Universitätsklinikum Münster [Munster, Germany], Goethe-University, Goethe-Universität Frankfurt am Main, Center for Cancer Rearch [Bethesda, MA, USA], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), University Children's Hospital [Freiburg, Germany], Department of Pediatrics and Department of Pathology [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Pathology [Ann Arbor, MI, USA] (Medical School), Huntsman Cancer Institute [Salt Lake City], University of Utah, University of Valencia, Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen [Germany], Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology and Children’s Research Center [Zurich, Switzerland], University Children’s Hospital Zurich, CRS Development of Biomolecular Therapies [Bologna, Italy] (Experimental Oncology Lab), University of Bologna-The Rizzoli Institute [Bologna, Italy], Department of Molecular Oncology [British Columbia, Canada], British Columbia Cancer Research Centre [British Columbia, Canada], Children's Cancer Research Center [Halle, Germany], Georgetown Lombardi Comprehensive Cancer Center, University Children's Hospital of Essen, Klinikum rechts der Isar [Munich, Germany]-Technical University and Comprehensive Cancer Center Munich - CCCM [Germany], TIRODE, Franck, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University Hospital Erlangen = Uniklinikum Erlangen, University of Bologna/Università di Bologna-The Rizzoli Institute [Bologna, Italy], and Widemann, BC
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Epigenomics ,Cancer Research ,Alternative medicine ,Medizin ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Review Article ,Bioinformatics ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,drug screen ,0302 clinical medicine ,Drug screen ,Cancer genomics ,signalling ,Sarcomagenesis ,0303 health sciences ,sarcomagenesis ,Summit ,geography.geographical_feature_category ,Opinion leadership ,Genomics ,Laboratory results ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,animal models ,3. Good health ,Animal models ,Metastatic Ewing Sarcoma ,Oncology ,030220 oncology & carcinogenesis ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Epigenetics ,Sarcoma ,Immunotherapy ,Prioritization ,medicine.medical_specialty ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,lcsh:RC254-282 ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,medicine ,genomics ,030304 developmental biology ,Medical education ,geography ,epigenetics ,business.industry ,biomarkers ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Clinical trial ,prognosis ,business ,Biomarkers ,Ewing sarcoma - Abstract
This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License.-- et al., The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials.
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- 2012
24. Cell Death Identification in Anticancer Therapy—Response
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David Herrero-Martin, Roser López-Alemany, Oscar M. Tirado, and Santiago Rello-Varona
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Oncology ,Cancer Research ,medicine.medical_specialty ,Programmed cell death ,Clonogenic survival ,Therapy response ,Apoptosis ,Internal medicine ,medicine ,Identification (biology) ,Pharmacology ,Biology - Abstract
We would like to thank Brown and colleagues ([1][1]) for their effort and their valuable comments on our review about cell death mechanisms in anticancer therapy. We understand their view on assessing the persistence of clonogenic survival from quantification of death records in anticancer research
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- 2015
25. Abstract 3080: Definition of the Ewing sarcoma specific oncomir-1 targetome
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Maximilian Kauer, David Herrero-Martin, Heinrich Kovar, and Raphaela Schwentner
- Subjects
Genetics ,Cancer Research ,Candidate gene ,Gene knockdown ,Oncology ,ETS transcription factor family ,microRNA ,Gene expression ,Ectopic expression ,Oncomir ,Biology ,E2F Transcription Factor Family - Abstract
MicroRNAs (miRNA) serve to fine-tune gene expression and thus play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a given tissue still poses a significant problem, since the presence of a seed sequence in the 3´UTR of an mRNA and its expression modulation upon forced ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. Here, we used a combination of AGO2 pull-down experiments by PAR-CLIP - to enrich and sequence RISC-associated RNAs - and of RNAseq upon miRNA depletion by ectopic sponge expression, to identify the targetome of miR17-92 in Ewing sarcoma (ES) cells. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in ES. As an aberrant ETS transcription factor it directly deregulates a multitude of genes related to proliferation control and differentiation. Recently, we reported on the EWS-FLI1 microRNA (miRNA) signature based on knockdown experiments in ES cell lines and on differential expression in primary tumors versus mesenchymal stem cells. Comparison of both datasets revealed miR20a-3p to be the top EWS-FLI1 activated miRNA. MiR-20a belongs to the miR17-92 cluster, also known as oncomir-1, which is one of the most potent oncogenic miRNAs. The whole cluster is among the small number of miRNAs down-regulated upon knockdown of EWS-FLI1 in multiple ES cell lines. Since feedback loops exists between the E2F transcription factor family and miR-17-92 and between EWS-FLI1 and E2F3, we sought to investigate the role of this miRNA cluster in ES. We found a significant enrichment of PAR-CLIP hits for members of the miR-17-92 cluster, in the 3´UTRs of genes up-regulated in response to mir-17-92 specific sponge expression. Among them we consistently identified known (i.e. CTGF, MXD1, CYLD1) and a multitude of so far unknown targets of the oncomir-1 cluster in ES in three PAR-CLIP experiments. Preliminary experiments using 3′UTRs of select novel candidate genes in gene reporter assays showed up-regulation of luciferase activity upon transfection of a sponge specific to miR-17-92 and 20a, but not to unrelated miR-9 and 10b. Site directed mutagenesis of seed sequences in the 3′UTR of these candidate genes will be used for further validation. This study provides an example for the comprehensive definition of the targetome for a defined group of miRNAs under physiological conditions. This study was supported by the 7th framework program of the European Commission (FP7-259348, “ASSET”) and the Austrian Science Fund FWF (24708-B21) Citation Format: Raphaela Schwentner, David Herrero-Martin, Maximilian Kauer, Heinrich Kovar. Definition of the Ewing sarcoma specific oncomir-1 targetome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3080. doi:10.1158/1538-7445.AM2015-3080
- Published
- 2015
26. Insulin-like growth factor I receptor pathway inhibition by ADW742, alone or in combination with imatinib, doxorubicin, or vincristine, is a novel therapeutic approach in Ewing tumor
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M J Campos, Jose-Luis Ordóñez, Ana Sofia Martins, Enrique de Alava, Teresa Hernández, Carlos Mackintosh, and David Herrero Martin
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Cancer Research ,medicine.medical_treatment ,Down-Regulation ,Apoptosis ,Bone Neoplasms ,Sarcoma, Ewing ,Biology ,Piperazines ,Receptor, IGF Type 1 ,Structure-Activity Relationship ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pyrroles ,Phosphorylation ,Autocrine signalling ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Insulin-like growth factor 1 receptor ,Dose-Response Relationship, Drug ,Cell growth ,TOR Serine-Threonine Kinases ,Growth factor ,Cell Cycle ,G1 Phase ,Cell cycle ,Pyrimidines ,Imatinib mesylate ,Oncology ,Doxorubicin ,Vincristine ,Benzamides ,Imatinib Mesylate ,Cancer research ,Drug Screening Assays, Antitumor ,Protein Kinases ,Proto-Oncogene Proteins c-akt - Abstract
[Purpose]: Ewing tumor cell survival and proliferation depends on several autocrine loops. Targeting these loops is a promising therapeutic approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and in this study, we intend to analyze the inhibition of the insulin-like growth factor I receptor (IGF1R) loop. [Experimental Design]: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib, vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway phosphorylation, soft-agar growth, motility, and vascular endothelial growth factor expression levels. [Results]: Treatment with ADW742 induced down-regulation of IGF1R/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation (IC50 = 0.55-1.4 μmol/L), inducing a G 1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions. [Conclusions]: Inhibition of Ewing tumor cell proliferation by ADW742 is mediated through blockade of IGF1R signaling. Combination of ADW742 with imatinib, vincristine, and doxorubicin induces a significant reduction of tumor cell growth, mainly by the increase in apoptosis with a pattern depending on IGF1R activation levels. This study supports a potential role for ADW742 in the treatment of Ewing tumor and AKT/mTOR as a possible surrogate marker of response to therapy. © 2006 American Association for Cancer Research., Grant support: Instituto de Salud Carlos III, Feder Madrid, Spain grants PI020828, G03-089, and C03-010 and III Quadro Comunitário de Apoio from the European Social Fund and Portuguese National Funds of the Ministry for Science and Higher Education.
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- 2006
27. Abstract 3966: PLK1 regulates PAX3-FOXO1 stability and its inhibition mediates regression of alveolar rhabdomyosarcoma xenograft tumors
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Marco Wachtel, Regina Hecker, Beat W. Schäfer, Dominik Laubscher, Verena Thalhammer, Peter K. Bode, Laura A. Lopez-Garcia, and David Herrero-Martin
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Cancer Research ,Kinase ,Biology ,medicine.disease ,Bioinformatics ,PLK1 ,Fusion protein ,Oncology ,Cancer research ,Alveolar rhabdomyosarcoma ,medicine ,Phosphorylation ,Gene silencing ,Kinome ,Transcription factor - Abstract
Oncogenic addiction provides an opportunity to develop new treatment options, especially for childhood cancers. Pediatric tumors contain a lower number of oncogenic mutations compared to most adult cancers, suggesting stronger dependency on individual oncogenes, such as chimeric transcription factors that have the ability to control multiple oncogenic pathways. Taking advantage of this addiction, targeting of oncogenic transcription factors becomes a new powerful strategy for therapy of translocation positive pediatric tumors like alveolar rhabdomyosarcoma (aRMS), which is characterized by a very dismal prognosis. As transcription factors are considered to be difficult to target, we developed an approach to screen for druggable upstream regulators like kinases. In two parallel activity reporter assays, using a kinome siRNA library and a small molecule library, we identified PLK1 to contribute to the activity of PAX3-FOXO1, the oncogenic transcription factor specific to aRMS. Mechanistically, we were able to demonstrate a direct interaction of the two proteins by co-immunoprecipitation. PLK1 silencing or inhibition increased degradation of PAX3-FOXO1, which suggests a stabilization of PAX3-FOXO1 due to phosphorylation by PLK1. Candidate phosphorylation sites were identified by in vitro kinase assays and mass spectrometric analysis and site-specific mutagenesis is currently utilized to validate the impact of these sites on fusion protein turnover. To highlight PLK1 as therapeutic target in aRMS, in vivo treatment studies using the PLK1 inhibitor BI 2536 resulted in complete tumor regression in two aRMS xenograft mouse models. Finally, tissue microarray analysis of human aRMS tumor biopsies showed PLK1 to be overexpressed and predictive of overall survival. Hence, our preclinical studies validate PLK1 as highly relevant drug target in alveolar rhabdomyosarcoma, similar to recent findings in other pediatric tumors. Our data suggests that PLK1 inhibitors warrant further investigations to evaluate the potential to be translated into a clinical setting. Citation Format: Verena Thalhammer, David Herrero-Martin, Regina Hecker, Dominik Laubscher, Laura Lopez-Garcia, Marco Wachtel, Peter Bode, Beat Schäfer. PLK1 regulates PAX3-FOXO1 stability and its inhibition mediates regression of alveolar rhabdomyosarcoma xenograft tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3966. doi:10.1158/1538-7445.AM2014-3966
- Published
- 2014
28. Abstract 3048: The genome-wide contribution of microRNAs to gene regulation in Ewing sarcoma
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Jesper V. Olsen, Heinrich Kovar, Grzegorz Sienski, Robert Kralovics, Kristina B. Emdal, David Herrero-Martin, Argyrou Fourtouna, and Maximilian Kauer
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Genetics ,Regulation of gene expression ,Gene expression profiling ,Cancer Research ,Gene knockdown ,Oncology ,MRNA destabilization ,FLI1 ,microRNA ,Gene expression ,Cancer research ,Ectopic expression ,Biology - Abstract
The identification of microRNA (miR) targets within a given cellular context still poses a largely unsolved problem. MiR targets are predicted based on the presence of seed sequences in the 3'UTR of mRNAs. Target candidate lists are filtered assuming mRNA destabilization, and validated by artificially forcing ectopic expression of miR analogs, or by interfering with miR expression by antagomirs. However, the expression level and amplitude of physiological miR variations is much smaller than experimentally induced miR perturbations. Crosslinking and immuno precipitation (CLIP) followed by sequencing of bound RNA allows monitoring of dynamic changes in miR/mRNA occupancy of RISC. However, it is unclear if increased miR activity will lead to increased target read counts due to elevated RISC occupancy or to decreased read counts as a consequence of target destabilization. Ewing sarcoma (ES) expresses an oncogenic transcription factor, EWS/FLI1.To study the impact of miRs to the gene regulatory network downstream of EWS/FLI1, we used a combination of mRNA and miR expression profiling, ChIP-seq, PAR-CLIP of AGO2, AGO2 knockdown, and SILAC monitoring of proteome changes in an inducible EWS/FLI1 knockdown ES cell line. Our data suggest that EWS/FLI1 perturbs gene regulation primarily on the transcriptional level and miRs play only a modulatory role for gene expression. Furthermore EWS/FLI1 affects the expression of many miR biogenesis and miR activity as well as RISC associated proteins. Knockdown of EWS/FLI1 results in pronounced changes of miR specific PAR-CLIP spectra. Disabled RISC activity lead to only minor changes in genome-wide mRNA expression. Our results are consistent with a complex role of the miRNome in the fine tuning of gene regulatory networks in Ewing sarcoma. Supported by grants EU-FP7 259348 and Austrian Science Fund FWF 24708-B21. Citation Format: David Herrero-Martin, Maximilian Kauer, Kristina B. Emdal, Grzegorz Sienski, Argyrou Fourtouna, Robert Kralovics, Jesper V. Olsen, Heinrich Kovar. The genome-wide contribution of microRNAs to gene regulation in Ewing sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3048. doi:10.1158/1538-7445.AM2013-3048
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- 2013
29. Abstract LB-462: AGO2 PAR-CLIP suggests a shift in specific miRNA target spectra upon modulation of EWS-FLI1 in Ewing's sarcoma
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Grzegorz Sienski, David Herrero-Martin, Heinrich Kovar, Max Kauer, Robert Kralovics, and Argyro Fourtouna
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Regulation of gene expression ,Cancer Research ,Gene knockdown ,Oncology ,RISC complex ,ETS transcription factor family ,microRNA ,PAR-CLIP ,Biology ,Protein degradation ,Gene ,Molecular biology - Abstract
The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in Ewing's sarcoma family tumors (ESFT). As an aberrant ETS transcription factor it directly deregulates a multitude of genes related to proliferation control and differentiation. Recently, we reported on the EWS-FLI1 microRNA (miRNA) signature based on knockdown experiments in ESFT cell lines and on differential expression in primary tumors versus mesenchymal stem cells. In order to define the mRNA targets of EWS-FLI1 regulated miRNAs, we now performed pull-down experiments of AGO2 complexes after photoactivated ribonucleoside-enhanced cross-linking followed by NGS sequencing of associated mRNAs (PAR-CLIP). We obtained 92 Mio high quality reads of which 63 Mio were aligned to the reference genome. The genomic localization of these sequences demonstrated the specific enrichment of 3'UTRs (>17 fold). Among obtained reads, T to C conversions were highly enriched consistent with crosslinking via 4-thiouridine to AGO2 containing complexes. PAR-CLIP results indicate AGO2 binding next to miRNA seed sequences for 4695 and 5160 genes associated with 1876 and 1860 miRNAs in the presence and absence of EWS-FLI1, respectively. Strikingly, for individual miRNAs the mRNA target spectra drastically changed upon EWS-FLI1 knockdown. For instance, for the two top EWS-FLI1 signature miRNAs hsa-mir-145 and hsa-mir 424 a shift from genes involved in cell death and differentiation to protein activator activity, and from protein degradation and cell cycle control to protein kinases and protein phosphorylation was observed, respectively. Of note, a target shift was also observed for miRNAs that did not change in response to EWS-FLI1 knockdown. In addition for many specifc targets no correlation was observed between mRNA abundancy and the level of association with AGO2 as reflected by read counts. These data suggest that EWS-FLI1 perturbs post-translational gene regulation by changing access of the RISC complex to its target mRNAs. Supported by EC-FP7 grant 259348 “ASSET”. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-462. doi:1538-7445.AM2012-LB-462
- Published
- 2012
30. Abstract 271: Validation of Polo-like Kinase 1 as a novel therapeutic target in alveolar rhabdomyosarcoma
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Verena Thalhammer, Regina Hecker, David Herrero-Martin, Beat W. Schäfer, and Felix Niggli
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Cancer Research ,Kinase ,PAX3 ,Biology ,medicine.disease ,Oncogene Addiction ,Bioinformatics ,PLK1 ,Fusion protein ,Oncology ,Alveolar rhabdomyosarcoma ,medicine ,Kinome ,Transcription factor - Abstract
Oncogenic transcription factors are the second most frequently mutated class of proteins. They represent ideal therapeutic targets because oncogene addiction is common to a broad spectrum of tumors and their inhibition may help to develop further alternative treatment strategies to improve therapy and to minimize treatment related side effects. However, thus far it has not been possible to target these oncogenic transcription factors as they usually do not respond to small-molecule inhibition. As a model system we use alveolar rhabdomyosarcoma (aRMS), an aggressive childhood tumor, which often displays resistance to conventional chemo-and radiotherapy. aRMS is characterized by the expression of the tumor-specific chimeric transcription factor PAX3/FKHR that is essential for survival of tumor cells. This transcription factor is post-translationally modified by phosphorylation which is required for efficient transcriptional activity. We believe that identification of upstream protein kinases mediating PAX3/FKHR phosphorylation will be an efficient strategy to impair the activity of the oncogenic fusion protein and subsequently induce tumor cell specific apoptosis. Having performed both siRNA and kinase-inhibitor library screens against the human kinome, we claim that Polo-like Kinase 1 (PLK1) might represent a very attractive and specific potential therapeutic target in aRMS. Its inhibition by RNAi and the small-molecule inhibitor BI 2536 reduces PAX3/FKHR activity and consequently aRMS cell viability. Moreover drug treatment causes tumor regression in xenograft mouse models. Therefore we are elucidating mechanisms causing these antitumorigenic effects and especially focus on the interaction of PLK1 and PAX3/FKHR. Our data suggest that PLK1 warrants further investigations as a novel drug target for the treatment of aRMS and may lead to a general strategy for treatment of tumors addicted to post-translationally modified oncogenic transcription factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 271. doi:1538-7445.AM2012-271
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- 2012
31. The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition
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Cristina Oliveira-Mateos, Anaís Sánchez-Castillo, Marta Soler, Aida Obiols-Guardia, David Piñeyro, Raquel Boque-Sastre, Maria E. Calleja-Cervantes, Manuel Castro de Moura, Anna Martínez-Cardús, Teresa Rubio, Joffrey Pelletier, Maria Martínez-Iniesta, David Herrero-Martín, Oscar M. Tirado, Antonio Gentilella, Alberto Villanueva, Manel Esteller, Lourdes Farré, and Sonia Guil
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Science - Abstract
RPSAP52 is an antisense-transcribed pseudogene of HMGA2 that positively regulates HMGA2 expression. Here, the authors show that reexpression of RPSAP52 promotes tumorigenicity by facilitating IGF2BP2 binding to its mRNA targets and consequently regulates the balance of LIN28B and let-7 levels.
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- 2019
- Full Text
- View/download PDF
32. Caveolin-1 is down-regulated in alveolar rhabdomyosarcomas and negatively regulates tumor growth
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David Herrero-Martin, Yaiza Núñez-Álvarez, Manel Esteller, Xavier Garcia del Muro, Miguel A. Peinado, Santiago Rello-Varona, Jaume Mora, Roser López-Alemany, Juan Huertas-Martinez, Josep Roma, Nuria Toran, Silvia Mateo-Lozano, Ignasi Barrau, Sebastian Moran, Oscar M. Tirado, Silvia Garcia-Monclús, Laura Lagares-Tena, Soledad Gallego, and Miguel Sáinz-Jaspeado
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Epigenomics ,Pathology ,medicine.medical_specialty ,alveolar rhabdomyosarcoma ,Tumor suppressor gene ,Caveolin 1 ,Down-Regulation ,Mice, Nude ,Transfection ,Mice ,Caveolin-1 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Rhabdomyosarcoma ,Clonogenic assay ,Rhabdomyosarcoma, Alveolar ,Cell Proliferation ,Tumors ,Regulation of gene expression ,5-AZA-2′-deoxycytidine ,epigenetics ,Cell Death ,business.industry ,Cell Differentiation ,Genetic Therapy ,medicine.disease ,Patologia ,Metabolisme ,Gene Expression Regulation, Neoplastic ,Metabolism ,Oncology ,muscular differentiation ,DNA methylation ,Cancer research ,Alveolar rhabdomyosarcoma ,Heterografts ,Signal transduction ,business ,Research Paper ,Signal Transduction - Abstract
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with histological variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of less than 30%. Caveolin-1 (CAV1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signaling. In the present study we report that compared to other forms of rhabdomyosarcoma (RMS) CAV1 expression is either undetectable or very low in ARMS cell lines and tumor samples. DNA methylation analysis of the promoter region and azacytidine-induced re-expression suggest the involvement of epigenetic mechanisms in the silencing of CAV1. Reintroduction of CAV1 in three of these cell lines impairs their clonogenic capacity and promotes features of muscular differentiation. In vitro, CAV1-expressing cells show high expression of Caveolin-3 (CAV3), a muscular differentiation marker. Blockade of MAPK signaling is also observed. In vivo, CAV1-expressing xenografts show growth delay, features of muscular differentiation and increased cell death. In summary, our results suggest that CAV1 could function as a potent tumor suppressor in ARMS tumors. Inhibition of CAV1 function therefore, could contribute to aberrant cell proliferation, leading to ARMS development.
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