Historical
 
Grupo de Epigenética del Cáncer  
Dr Manel Esteller

Grupo de Epigenética del Cáncer
Group Leader: Dr Manel Esteller



 
  RESEARCH TEAMS  
 

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Dr Manel Esteller

Grupo de Epigenética del Cáncer
 

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Dra. Montse Sanchez-Cespedes

Grupo de Genes y Cáncer
 

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Dr .Alejandro Vaquero

Grupo de Biología de la Cromatina
 

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Dr. Esteban Ballestar

Grupo de Cromatina y Enfermedad
 

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Dra. Ethel Queralt

Grupo de Ciclo Celular
 

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Dr. Dave Monk

Grupo de Impronta Genómica y Cáncer
 

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Dra. Maribel Parra

Grupo de Diferenciación Celular
 

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Dra. Purificación Muñoz

Grupo de Envejecimiento y Cáncer
 

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Dra. Eva Gonzalez-Suarez

Grupo de Transformación y Metástasis
 

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PEBC

Apoyo Genómico
 

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PEBC

Apoyo bioinformático
 

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PEBC

Apoyo Administrativo a la Investigación
 

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PEBC

Servicio de Apoyo
 
 
     
  Group description

Our main interests are:

-Definition of the Epigenome of Cancer Cells: Profile of DNA methylation and histone modifications in tumor suppressor genes and repetitive sequences in cancer. Global and gene-specific definition of aberrant epigenetic changes and functional consequences in transcription regulation, DNA repair and chromosome instability.


-Study of the Epigenetics Machinery and Mechanisms: Role and function of DNA methyltransferases (enzymes that maintain DNA methylation), specificity of methyl-CpG binding domain proteins (the nuclear factors that recognize DNA methylation), analysis of biological properties of histone deacetylases and methyltransferases (enzymes that modify histones).


-Study of Mutations in the Epigenetic Machinery: The mechanisms underlying the disruption of the epigenetic landscape in transformed cells are unknown. It is possible that the enzymes that epigenetically modify DNA and histone are themselves targets of genetic disruption. Mutational analysis of "epigenetic modifier genes".


- Testing of Epigenetic Drugs: Study of the biological effects in cell lines and mouse models of different small epigenetic drugs directed against DNA methylatransferases, histone deacetylases and other enzymes of the epigenetic machinery. Analysis of their use as anticancer drugs.

Overview of research:

Cancer is an epigenetic disease characterized by the breakdown of the DNA methylation and histone modification patterns. The stability of our genome and correct gene expression are maintained in large measure thanks to a perfectly pre-established pattern of DNA methylation and histone modifications. In cancer, this ideal scenario is destroyed by the occurrence of an interesting phenomenon whereby the regulatory regions (CpG islands) of certain tumor suppressor genes become hypermethylated, inactivating the gene as a consequence, whilst a wave of hypomethylation occurs in the genome. We have developed procedures (Chip-on-CHIP, MeDIP…) for massive genomic screening to find new hypermethylated genes in cancer cells and characterize their histone codes. Both DNA methylation and histone modiffications control the activity of a third component of the epigenetic landscape, non-coding RNAs, particularly microRNAs that are also disrupted in human cancer.


Recent research achievements:

-Construction of epigenomic maps in health and disease: An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. We have previously explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among our results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide - an approach that we have taken to provide both biological insight and new avenues for translational research. This "upgrade" of cancer epigenetics research represent the backone for the future obtention of the first complete epigenomes that include DNA methylomes and histone modification maps (Esteller, Nat Rev Genet, 2007).

-Discovery of the DNA-methylation mediated silencing of microRNAs. In the last few years, microRNAs have started a revolution in molecular biology and emerged as key players in the cancer process. For these reasons, it is extremely important to understand the physiological and disease-associated mechanisms underlying the regulation of these small, single-stranded RNAs. Thus, it was merely a matter of time before microRNAs and epigenetics coincided (Lujambio et al., Cell Cycle, 6, 1455-1459 2007). The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can "hit" miRNAs in transformed cells. To address this issue, we used cancer cells genetically deficient for the DNA methyltransferase enzymes in combination with a miRNA expression profiling. We have observed that DNA hypomethylation induces a release of miRNA silencing in cancer cells (Lujambio et al., Cancer Res., 67, 1424-1429, 2007) (Figure 2). One of the main targets is miRNA-124a, which undergoes transcriptional inactivation by CpG island hypermethylation in human tumors from different cell types. Interestingly, we functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene.

-DNA methylation as a caretaker of nucleolar structure. The nucleolus is the site of ribosome synthesis in the nucleus, whose integrity is essential. We have shown that human cells lacking DNA methyltransferase 1 (Dnmt1), but not Dnmt3b, have a loss of DNA methylation and an increase in the acetylation level of lysine 16 histone H4 at the rRNA genes. Interestingly, we observed that SirT1, a NAD+-dependent histone deacetylase with a preference for lysine 16 H4, interacts with Dnmt1; and SirT1 recruitment to the rRNA genes is abrogated in Dnmt1 knockout cells. The DNA methylation and chromatin changes at ribosomal DNA observed are associated with a structurally disorganized nucleolus, which is fragmented into small nuclear masses. These findings suggest a role for Dnmt1 as an epigenetic caretaker for the maintenance of nucleolar structure (Espada et al., Nuc. Acids Res., 35, 2191-2198, 2007).

-Development of new epigenomic techniques to unmask tumor suppressor genes in human cancer. New large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells (Esteller, Hum. Mol. Genet., 16, R50-59, 2007). We have reported a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKO cells). Using methylated DNA immunoprecipitation methodology in conjunction with promoter microarray analyses, we found that DKO cells experience a significant loss of hypermethylated CpG islands (Jacinto et al., Cancer Res., 67, 11481-11486, 2007). Further characterization of these candidate sequences shows CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine nucleotide-releasing factor (RASGRF2), the apoptosis-associated basic helix-loop transcription factor (BHLHB9), and the homeobox gene (HOXD1). Hypermethylation of these genes occurs in premalignant lesions and accumulates during tumorigenesis. Thus, our results show the usefulness of DNMT genetic disruption strategies combined with methylated DNA immunoprecipitation in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use.




Our main interests are:

-Definition of the Epigenome of Cancer Cells: Profile of DNA methylation and histone modifications in tumor suppressor genes and repetitive sequences in cancer. Global and gene-specific definition of aberrant epigenetic changes and functional consequences in transcription regulation, DNA repair and chromosome instability.

-Study of the Epigenetics Machinery and Mechanisms: Role and function of DNA methyltransferases (enzymes that maintain DNA methylation), specificity of methyl-CpG binding domain proteins (the nuclear factors that recognize DNA methylation), analysis of biological properties of histone deacetylases and methyltransferases (enzymes that modify histones).

-Study of Mutations in the Epigenetic Machinery: The mechanisms underlying the disruption of the epigenetic landscape in transformed cells are unknown. It is possible that the enzymes that epigenetically modify DNA and histone are themselves targets of genetic disruption. Mutational analysis of "epigenetic modifier genes".

- Testing of Epigenetic Drugs: Study of the biological effects in cell lines and mouse models of different small epigenetic drugs directed against DNA methylatransferases, histone deacetylases and other enzymes of the epigenetic machinery. Analysis of their use as anticancer drugs.


  Leader Bio
 
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Manel Esteller (Sant Boi de Llobregat, Barcelona, Cataluña, España, 1968) se graduó en Medicina con honor por la Universidad de Barcelona en 1992, donde obtuvo también su Doctorado especializado en Genética Molecular del Carcinoma del Endometrio, en 1996. Fue Investigador Invitado en la Escuela de Ciencias Biológicas y Médicas de la Universidad de St. Andrews, (Escocia, Reino Unido), donde centró su investigación en el estudio de la genética molecular del cáncer de mama hereditario.

De 1997 a 2001, Esteller fue Investigador Posdoctoral e Investigador Asociado en la Escuela de Medicina de la Universidad Johns Hopkins (Baltimore, EEUU) donde estudió la metilación del ADN y su relación con el cáncer en humanos. Sus resultados han sido decisivos para establecer que la hipermetilación de los genes supresores de tumores es un sello característico de los tumores humanos. Desde octubre del 2001 a septiembre del 2008, Manel Esteller ha liderado el Laboratorio de Epigenética del Cáncer del CNIO. Durante este tiempo se ha dedicado a la investigación de las alteraciones de la metilación del ADN, las modificaciones de las histonas y la  cromatina y su contribución al cáncer en humanos. Desde octubre del 2008, el Dr. Esteller es el Director del Programa de Epigenética y Biología del Cáncer del Instituto de Investigaciones Biomédicas de Bellvitge (IDIBELL) en Barcelona y Jefe del Grupo de Epigenética del Cáncer. Su investigación actual se centra en el establecimiento de los mapas epigenómicos de células normales y transformadas, el estudio de las modificaciones epigenéticas y los ARNs no codificantes, así como en el desarrollo de nuevos medicamentos epigenéticos para tratar el cáncer.

Es autor de más de doscientos sesenta manuscritos originales, acreditados en el ámbito de las ciencias biomédicas, es miembro de numerosas sociedades científicas internacionales, de editoriales y crítico de varias revistas y entidades patrocinadoras. El Dr. Esteller es también editor asociado de las revistas “Cancer Research“ , “The Lancet Oncology and Carcinogenesis“, redactor jefe de “Epigenetics” y asesor de “The Human Epigenome Project”, miembro asociado de “The Epigenome Network of Excellence” y presidente de la Sociedad de Epigenética. Ha recibido numerosos premios incluyendo:  el Premio al Mejor Investigador Joven en Cáncer otorgado por la Escuela Europea de Oncologó Médica (the European School of Medical Oncology) en 1999, el Primer Premio en Investigación Básica en la Universidad e Institución Médica Johns Hopkins (1999), el Premio al Mejor Investigador Joven de la Asociación Europea para la Investigación del Cáncer (2000), el Premio al Investigador Joven de la Asociación Americana para la Investigación del Cáncer (American Association for Cancer Research)-AFLAC (2001), el Premio Carcinogenesis (2005), el Premio Beckman-Coulter  (2006), el Premio a la Investigación Biomédica Francisco Cobos (2006), el Premio de la “Fondazione Piemontese per la Ricerca sul Cancro (FPRC)” (2006), el Premio “Swiss Bridge” (2006), el Premio a la Investigación Nacional en Oncología "Maria Julia Castillo" (2007), el Premio "Dr. Josep Trueta" de la Academia de Ciencias Médicas de Cataluña (2007), el Premio a la Innovación del “Commonwealth of Massachussets” (2007), el Premio del Programa “Human Frontier Science” (2007), el premio de la Fundación Dr. Jacint Vilardell  (2008), Debiopharm-EPFL Award (2008), Josef Steiner Cancer Research Award (2009), el Premio de Investigación Biomédica Preclinica de la Fundación Lilly (2009) y el Premio de la Cumbre Mundial de la Salud (2010).


El Dr. Manel Esteller es el Director del Programa de Epigenética y Biología del Cáncer del Instituto de Investigaciones Biomedicas de Bellvitge (IDIBELL) y Jefe del Grupo de Epigenética del Cáncer, así como Profesor de Genética de la Escuela de Medicina de la Universidad de Barcelona y Profesor de Investigación ICREA.



       
  Selected publications

 

 flecha Heyn H, Moran S, Hernando-Herraez I, Sayols S, Gomez A, Sandoval J, Monk D, Hata K, Marques-Bonet T, Wang L, Esteller M. DNA methylation contributes to natural human variation. Genome Research, 23, 1363-72, 2013

 flecha Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR. Global Epigenomic Reconfiguration During Mammalian Brain Development. Science, 341, 1237905, 2013

 flecha Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Plata I, Formiga F, Fernandez AF, Fraga MF, Heath S, Valencia A, Gut IG, Wang J, Esteller M. The Distinct DNA Methylomes of Newborns and Centenarians. Proc Natl Acad Sci USA, 109, 10522-7, 2012

 flecha Guil S, Soler M, Portela A, Carrère J, Fonalleras E, Gómez A, Villanueva A, Esteller M. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nature Structural & Molecular Biology, 19, 664-70, 2012.

 flecha Fernandez AF, Assenov Y, Martin-Subero JI, Balint B, Siebert R, Taniguchi H, Yamamoto H, Hidalgo M, Tan AC, Galm O, Ferrer I, Sanchez-Cespedes M, Villanueva A, Carmona FJ, Sanchez-Mut JV, Berdasco M, Moreno V, Capella G, Monk D, Ballestar E, Ropero S, Martinez R, Sanchez-Carbayo M, Prosper F, Agirre X, Fraga MF, Graña O, Perez-Jurado L, Mora J, Puig S, Prat J, Badimon L, Puca AA, Meltzer SJ, Lengauer T, Bridgewater J, Bock C, Esteller M. A DNA Methylation Fingerprint of 1,628 Human Samples. Genome Research, May 25, 2011.

 flecha Melo S, Villanueva A, Moutinho C, Davalos V, Spizzo R, Ivan C, Rossi S, Setien F, Casanovas O, Sio-Riudalbas L, Carmona FJ, Carrere J, Vidal A, Aytes A, Puertas S, Ropero S, Kalluri R, Croce CM, Calin GA, Esteller M. The small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. Proc Natl Acad Sci USA, 108, February 28th, 2011.

 flecha Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernandez AF, Davalos V, Villanueva A, Yamamoto H, Schwartz Jr, Esteller M. A Genetic Defect in Exportin-5 Traps Precursor MicroRNAs in the Nucleus of Cancer Cells. Cancer Cell, 18, 303–15, 2010.

 flecha Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, Lossone R, Alaminos M, Cheung NK, Rahmanh N, Esteller M. Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci USA, 106, 21830-35, 2009.

 flecha Melo SA, Ropero S, Moutinho C, Aaltonen LA, Yamamoto H, Calin GA, Rossi S, Fernandez AF, Carneiro F, Oliveira C, Ferreira B, Liu CG, Villanueva A, Capella G, Schwartz Jr S, Shiekhattar R, Esteller M. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nature Genetics, 41, 365-70, 2009.

 flecha Fernandez AF, Rosales C, Lopez-Nieva P, Graña O, Ballestar E, Ropero S, Espada J, Melo SA, Lujambio A, Fraga MF, Pino I, Javierre B, Carmona FJ, Acquadro F, Steenbergen RDM, Snijders PJF, Chris J. Meijer, Pascal Pineau, Anne Dejean, Lloveras B, Capella G, Quer J, Buti M, Esteban JI, Allende H, Rodriguez-Frias F, Castellsague X, Minarovits J, Ponce J, Capello D, Gaidano G, Cigudosa JC, Gomez-Lopez G, Pisano DG, Valencia A, Piris MA, Bosch FX, Cahir-McFarland E, Kieff E, Esteller M. The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Research, 323, 1600-4, 2009.

 flecha Teixeira FK, Heredia F, Sarazin A, Roudier F, Boccara M, Ciaudo C, Cruaud C, Poulain J, Berdasco M, Fraga MF, Voinnet O, Wincker P, Esteller M, Colot V. A Role for RNAi in the Selective Correction of DNA Methylation Defects. Science 323, 1600-4, 2009.

 flecha Ballestar E, Esteller M. SnapShot: the human DNA methylome in health and disease. Cell, 135, 1144-1144.e1, 2008.

 flecha Lujambio A, Calin GA, Villanueva A, Ropero S, Sánchez-Céspedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, Gallagher WM, Eccles SA, Croce CM, Esteller M. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA, 105, 13556-61, 2008.

 flecha Esteller M. Epigenetics in cancer. New England Journal of Medicine, 358, 1148-1159, 2008.

 flecha Esteller M. Cancer epigenomics: DNA methylomes and histone modification maps. Nature Reviews Genetics, 8, 286-98, 2007.

 flecha Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, Casado S, Suarez-Gauthier A, Montserrat Sanchez-Cespedes M, Gitt A, Spiteri I, Das PP, Caldas C, Miska E, Esteller M. Genetic Unmasking of an Epigenetically Silenced microRNA in Human Cancer Cells. Cancer Research, 67, 1424-9, 2007.

 flecha Agrelo R, Cheng WS, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci USA. 102, 103, 8822-7, 2006.

 flecha Ropero S, Fraga MF, Ballestar E, Hamelin R, Yamamoto H, Boix-Chornet M, Caballero R, Alaminos M, Setien F, Paz MF, Herranz M, Palacios J, Arango D, Orntoft TF, Aaltonen LA, Schwartz Jr S., Esteller M. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nature Genetics, 38, 566-9, 2006.

 flecha Vire E, Brenner C, Deplus R, Blanchon L, Fraga MF, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, Launoit Y, Fuks F. The Polycomb Group protein EZH2 controls DNA methylation through association with DNA methyltransferases. Nature, 439, 871-874, 2006.

 flecha Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 102, 10604-10609, 2005

 flecha Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Pérez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M. Loss of acetylated lysine 16 and trimethylated lysine 20 of histone H4 is a common hallmark of human cancer. Nature Genetics, 37, 391-400, 2005.

 flecha Chen WY, Zeng X, Carter MG, Morrell CN, Yen RWC, Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB. Heterozygous disruption of Hic-1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nature Genetics, 33, 197-202, 2003.

 flecha Hedelfank I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J. Gene-expression profiles in hereditary breast cancer. New England Journal of Medicine 343, 539-48, 2001

 flecha Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG. Activity of the DNA repair gene MGMT and the clinical response of gliomas to alkylating agents. New England Journal of Medicine 343, 1350-4, 2000.


 

  Members
NAME E-MAIL URL

Dr. Manel Esteller

 Director

mesteller@idibell.cat

Dra. Dori Huertas

 Investigador Asociado

dhuertas@idibell.cat

Dra. Maria Berdasco

 Investigador Asociado

mberdasco@idibell.cat

Dra. Sonia Guil

 Investigador Asociado

sguil@idibell.cat

Dr. Angel Díaz

 Investigador Postdoctoral

adiaz@idibell.cat

Dr. Geert van Tetering

 Investigador Postdoctoral

gvantetering@idibell.cat

Dr. Holger Heyn

 Investigador Postdoctoral

hheyn@idibell.cat

Dr. Jesús Méndez

 Investigador Postdoctoral

jmendez@idibell.cat

Dr. Juan Sandoval

 Investigador Postdoctoral

jsandoval@idibell.cat

Dr. Mauricio Saez

 Investigador Postdoctoral

msaez@idibell.cat

Dr. Yutaka Hashimoto

 Investigador Postdoctoral

yhashimoto@idibell.cat

Dra. Ana Belén Crujeiras

 Investigador Postdoctoral

acrujeiras@idibell.cat

Dra. Anna Martínez

 Investigador Postdoctoral

amartinezc@idibell.cat

Dra. Anna Portela

 Investigador Postdoctoral

aportela@idibell.cat

Dra. Paula López

 Investigador Postdoctoral

plopez@idibell.cat

Dra. Verónica Dávalos

 Investigador Postdoctoral

vdavalos@idibell.cat

Alexia Martínez

 Estudiante de Doctorado

amartinezd@idibell.cat

Carmen Anadón

 Estudiante de Doctorado

canadon@idibell.cat

Humberto Gomes Ferreira

 Estudiante de Doctorado

hgomes@idibell.cat

Javier Carmona

 Estudiante de Doctorado

fjcarmona@idibell.cat

Jose Sánchez-Mut

 Estudiante de Doctorado

jvsanchez@idibell.cat

Julia Liz

 Estudiante de Doctorado

jliz@idibell.cat

Laia Simó

 Estudiante de Doctorado

lsimo@idibell.cat

Miguel Vizoso

 Estudiante de Doctorado

mvizoso@idibell.cat

Paolo Petazzi

 Estudiante de Doctorado

ppetazzi@idibell.cat

Raquel Boqué

 Estudiante de Doctorado

rboque@idibell.cat

Vanesa Nogales

 Estudiante de Doctorado

vnogales@idibell.cat

Fernando Setién

 Técnico Superior

fsetien@idibell.cat

Marta Soler

 Técnico Superior

msoler@idibell.cat

Olga de la Caridad Jorge

 Técnico Superior

ocjorge@idibell.cat

Catia Moutinho

 Técnico

cmoutinho@idibell.cat

Laura Roa

 Técnico

lroa@idibell.cat

Miguel López

 Técnico

mlopez@idibell.cat

 
 

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