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Investigación
Unidad de Tumores Sólidos Infantiles
Líneas de investigación
Content with Investigacion .
Identificación y caracterización funcional de genes diana de la oncoproteína EWSR1::FLI1 característica de los sarcomas de Ewing
Los sarcomas de Ewing son un tipo de tumores de la infancia y la adolescencia que se caracterizan por la presencia de translocaciones cromosómicas que dan lugar a factores de transcripción quiméricos. La más frecuente de estas alteraciones cromosómicas fusiona el gen EWSR1 con el gen FLI1, dando lugar al factor de transcripción aberrante EWSR1::FLI1. EWSR1::FLI1 desempeña un papel fundamental en el desarrollo del sarcoma de Ewing, ya que regula la expresión de centenares de genes implicados en el proceso tumoral. En nuestro laboratorio combinamos el uso de tecnologías shRNA y CRISPR/Cas9 para generar modelos de enfermedad con las técnicas más avanzadas de análisis genómico y proteómico para identificar los genes implicados en el desarrollo del sarcoma de Ewing. El objetivo final es identificar genes diana que permitan el desarrollo y diseño de terapias dirigidas más eficaces y con menos efectos secundarios.
Desarrollo de terapias avanzadas para el tratamiento del sarcoma de Ewing
El tratamiento estandar del sarcoma de Ewing se basa en el uso de quimioterapia, radioterapia y cirugía. Aunque estos tratamientos son relativamente eficaces para algunos tumores localizados, son totalmente ineficientes en el caso de pacientes con tumores metastásicos o resistentes a los tratamientos convencionales. Como consecuencia de la falta de alternativas terapéuticas eficaces, tres de cada cuatro niños o adolescentes con tumores metastásicos o refractarios morirán por causa de la enfermedad. Es por tanto urgente desarrollar nuevas terapias para dar respuesta a este grupo de pacientes. En nuestro laboratorio estamos trabajando en el desarrollo de terapias disruptivas, que representen un enfoque totalmente novedoso para el tratamiento de esta enfermedad. Nuestra apuesta se basa en el uso de aproximaciones de terapia génica y el uso de vectores virales (principalmente adenovirus) y no virales (principalmente nanopartículas lipídicas) para vehiculizar las terapias a las células tumorales.
Publicaciones destacadas
CREBBP/EP300 bromodomain inhibition affects the proliferation of AR positive breast cancer cell lines. (2019) Molecular Cancer Research. 17 (3): 720–730.
Garcia-Carpizo V, Ruiz-Llorente S, Sarmentero J, Gonzalez-Corpas A and Barrero MJ.
DOICREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation. (2018) Epigenetics and Chromatin 11:30.
Garcia-Carpizo V, Ruiz-Llorente S, Sarmentero J, Graña O, Pisano DG and Barrero MJ.
DOINSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation. (2016) Scientific Reports. 6:32952.
Garcia-Carpizo V, Sarmentero J, Han B, Graña O, Ruiz-Llorente S, Pisano DG, Serrano M, Brooks HB, Campbell RM, Barrero MJ.
DOISETD7 Regulates the Differentiation of Human Embryonic Stem Cells. (2016) PLoS One. 11(2): e0149502.
Castaño J, Morera C, Sesé B, Boue S, Bonet-Costa C, Martí M, Roque A, Jordan A, Barrero MJ.
DOIMacro Histone Variants are Critical for the Differentiation of Human Pluripotent Cells. (2013) Journal of Biological Chemistry. 288(22):16110-6.
Barrero MJ, Sese B, Marti M and Izpisua Belmonte JC.
DOIMacro Histone Variants Preserve Cell Identity by Preventing the Gain of H3K4me2 during Reprogramming to Pluripotency. (2013) Cell Reports 3, 1005–1011.
Barrero MJ, Sese B, Kuebler B, Bilic J, Boue S, Martí M, Belmonte JC.
DOIMediator-regulated transcription through the +1 nucleosome. (2012) Molecular Cell. 48(6):837-48.
Nock A, Ascano JA, Barrero MJ and Malik S.
DOIAlu-repeat mediated regulation of DIEXF expression in cell differentiation and cancer. (2020) Epigenetics 15(6-7):765-779.
Martín B, Pappa S. Díez-Villanueva A, Mallona I, Custodio J, Barrero MJ, Peinado MA, Jordà M.
DOIDNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders. Sci Rep. (2017) 7(1):11762.
Berdasco M, Gómez A, Rubio MJ, Català-Mora J, Zanón-Moreno V, Lopez M, Hernández C, Yoshida S, Nakama T, Ishikawa K, Ishibashi T, Boubekeur AM, Louhibi L, Pujana MA, Sayols S, Setien F, Corella D, de Torres C, Parareda A, Mora J, Zhao L, Zhang K, Lleonart ME, Alonso J, Simó R, Caminal JM, Esteller M.
PUBMED DOIEWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma. Oncogene (2017) 36(6):766-776.
Cidre-Aranaz F, Grünewald TG, Surdez D, García-García L, Carlos Lázaro J, Kirchner T, González-González L, Sastre A, García-Miguel P, López-Pérez SE, Monzón S, Delattre O, Alonso J.
PUBMED DOIFamilial retinoblastoma due to intronic LINE-1 insertion causes aberrant and non-canonical mRNA splicing of the RB1 gene. J Hum Genet (2016) 61(5):463-6.
Rodríguez-Martín C., Cidre-Aranaz F., Fernández-Teijeiro A., Gómez-Mariano G., de la Vega L., Ramos P., Zaballos A., Monzón S., Alonso J.
PUBMED DOIChimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA-microsatellite. Nature Genetics (2015) 47(9):1073-8.
Grünewald T.G.P., Bernard V., Gilardi-Hebenstreit P., Raynal V., Surdez D., Aynaud M.M., Mirabeau O., Cidre-Aranaz F., Tirode F., Zaidi S., Perot G., Jonker A.H., Lucchesi C., Le Deley M.C., Oberlin O., Marec-Bérard P., Véron A.S., Reynaud S., Lapouble E., Boeva V., Frio T.R, Alonso J., Bhatia S., Pierron G., Cancel-Tassin G., Cussenot O., Cox D.G., Morton L.M., Machiela M., Chanock S.J., Charnay P., Delattre O.
PUBMED DOISelective inhibition of plasma membrane calcium ATPase4 improves angiogénesis and vascular reperfusion. 2017. J. Mol. Cell. Cardiol. 109: 38-47.
Kurusamy S., López-Maderuelo D., Little R., Cadagan D., Savage A.M., Ihugba J.C., Baggott RR, Rowther FB., Martínez-Martínez S, Gómez-del Arco P., Murcott C., Wang W., Nistal F.J., Oceandy D, Neyses L, Wilkinson R.N., Cartwright EJ, Redondo J.M. and A.L. Armesilla.
PUBMED DOIThe Chromatin Remodeling Complex Chd4/NuRD controls striated muscle identity and metabolic homeostasis. 2016. Cell Metabolism. 23: 881-892.
Gómez-del Arco P*., Perdiguero E., Yunes-Leites P.S., Acín-Pérez R., Zeini M., García-Gómez A., Sreenivasan K., Jiménez-Alcázar M., Segalés J., López-Maderuelo D., Ornés B., Jiménez-Borreguero L.J., D´Amato G., Enshell-Seijffers D., Morgan B., Georgopoulos K., Islam AbuL B.M.M.K., Braun T., de la Pompa J.L., Kim J., Enriquez J.A., Ballestar E,, Muñoz-Cánoves P. and Redondo J.M*. *corresponding authors.
PUBMED DOISequential ligand-dependent Notch signaling activation regulates valve primordium formation and morphogenesis. 2016. Circulation Research. 118 (10): 1480-1497.
MacGrogan D., D´Amato G., Travisano S., Martinez-Poveda B., Luxán G., del Monte-Nieto G., Papoutsi T., Sbroggio M., Bou V., Gómez-del Arco P., Gómez M.J., Zhou B., Redondo J.M., Jiménez-Borreguero L.J., de la Pompa J.L.
PUBMED DOIPlasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. 2014. Arterioscler. Thromb. Vasc. Biol. Volumen: 34: 2310-2320.
Baggott RR, Alfranca A, López-Maderuelo D, Mohamed TM, Escolano A, Oller J, Ornes BC, Kurusamy S, Rowther FB, Brown JE, Oceandy D, Cartwright EJ, Wang W, Gómez-del Arco P, Martínez-Martínez S., Neyses L, Redondo JM, Armesilla AL.
PUBMED DOIAlternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis. 2010. Immunity. 33(5): 685-698.
Pablo Gómez-del Arco, Mariko Kashiwagi, Audrey F. Jackson, Taku Naito, Jiangwen Zhang, Feifei Liu, Barbara Kee, Marc Vooijs, Freddy Radtke, Juan Miguel Redondo and Katia Georgopoulos.
PUBMED DOIMAZ induces MYB expression during the exit from quiescence via the E2F site in the MYB promoter. 2017. Nucleic Acids Research. 45 (17): 9960-9975.
Alvaro-Blanco J., Urso K., Chiodo Y., Martín-Cortázar C., Kourani O., Gómez-del Arco P., Rodríguez-Martínez M., Calonge E., Alcamí J., Redondo JM., Iglesias T., and MR. Campanero.
PUBMED DOILiver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease
Gómez-Mariano G, Matamala N, Martínez S, Justo I, Marcacuzco A, Jimenez C, Monzón S, Cuesta I, Garfia C, Martínez MT, Huch M, Pérez de Castro I, Posada M, Janciauskiene S, Martínez-Delgado B. Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease. Hepatol Int. 2020 Jan;14(1):127-137.
PUBMED DOIThe Solve-RD Solvathons as a pan-European interdisciplinary collaboration to diagnose patients with rare disease.
Yépez VA, Demidov G, Ellwanger K, Laurie S, Luknárová R, Joseph Maran MI, Hentrich T, Sagath L, van der Sanden B, Astuti G, Neveling K, Batlle-Masó L, Beijer D, Brechtmann F, Caballero-Oteyza A, Dabad M, Denommé-Pichon AS, Doornbos C, Eddafir Z, Estévez-Arias B, Kilicarslan OA, Kolen IHM, Kraß L, Lohmann K, Londhe S, López-Martín E, Maassen K, Macken W, Martínez-Delgado B, Mei D, Mertes C, Minardi R, Morsy H, Mueller JS, Natera-de Benito D, Nelson I, Oud MM, Paramonov I, Picó D, Piscia D, Polavarapu K, Raineri E, Savarese M, Smal N, Steehouwer M, Steyaert W, Swertz MA, Thomsen M, Töpf A, Van de Vondel L, van der Vries G, Vitobello A, Wilke C, Zurek B; Solve-RD DITF-EPICARE; Solve-RD DITF-ITHACA; Solve-RD DITF-EURO-NMD; Solve-RD DITF-RITA; Solve-RD DITF-RND; Solve-RD consortium; T' Hoen PB, Matalonga L, Vissers LELM, Gilissen C, Schulze-Hentrich J, Beltran S, Esteve-Codina A, Hoischen A, Gagneur J, Graessner H. Nat Genet. 2025 Sep 9. doi: 10.1038/s41588-025-02290-3. Online ahead of print. PMID: 40926087 Review.
PUBMED DOIHeterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, ATP9A, Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual Disability.
Cordovado A, Hérenger Y, Cormier C, López-Martín E, Stamberger H, Faivre L, Denommé-Pichon AS, Vitobello A, Abdallah HH, Barcia G, Courtin T, Martínez-Delgado B, Bermejo-Sánchez E, Barrero MJ, Gasser B, Bezieau S, Küry S, Weckhuysen S, Laumonnier F, Toutain A, Vuillaume ML. Hum Mutat. 2025 Mar 5;2025:7085599. doi: 10.1155/humu/7085599. eCollection 2025. PMID: 40226306 Free PMC article.
PUBMED DOIAdult neurogenesis through glial transdifferentiation in a CNS injury paradigm
Casas-Tinto S, Garcia-Guillen N, Losada-Perez M. Adult neurogenesis through glial transdifferentiation in a CNS injury paradigm. Elife. 2025 Mar 7;13:RP96890. doi: 10.7554/eLife.96890. PMID: 40052673; PMCID: PMC11888597.
PUBMED DOIVP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context
Castello-Pons M, Ramirez-Gonzalez MA, Iglesias-Hernández P, Lendo NL, Rodriguez-Martín C, Quiralte L, Sepúlveda-Sánchez JM, de Dios O, Gil C, Martínez A, Sánchez-Gómez P, Casas-Tinto S. VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context. Neurotherapeutics. 2025 Jul;22(4):e00576. doi: 10.1016/j.neurot.2025.e00576. Epub 2025 Mar 28. PMID: 40157890; PMCID: PMC12418426.
PUBMED DOIThree Decades of the Spanish Society for Developmental Biology (SEBD): Insights and Emerging Perspectives from the 18th Spanish Society for Developmental Biology Meeting (SEBD 2024)
Herrera E, Acosta S, Almuedo M, Borrell V, Cañestro C, Casas-Tintó S, Escudero LM, Gorfinkiel N, Hoijman E, Pastor-Pareja JC, Pernaute B, Rayón T, Saade M, Solana J, Trivedi V, Martí E, Pujades C, Araújo SJ. Three Decades of the Spanish Society for Developmental Biology (SEBD): Insights and Emerging Perspectives from the 18th Spanish Society for Developmental Biology Meeting (SEBD 2024). Int J Dev Biol. 2025;69(1):1-9. doi: 10.1387/ijdb.250034sa. PMID: 40298871.
PUBMED DOIImmunodetection of Truncated Forms of the α6 Subunit of the nAChR in the Brain of Spinosad Resistant Ceratitis capitata Phenotypes
Guillem-Amat A, López-Errasquín E, García-Ricote I, Barbero JL, Sánchez L, Casas-Tintó S, Ortego F. Immunodetection of Truncated Forms of the α6 Subunit of the nAChR in the Brain of Spinosad Resistant Ceratitis capitata Phenotypes. Insects. 2023 Nov 4;14(11):857. doi: 10.3390/insects14110857. PMID: 37999056; PMCID: PMC10672392.
PUBMED DOISynaptic components are required for glioblastoma progression in Drosophila
Losada-Pérez M, Hernández García-Moreno M, García-Ricote I, Casas-Tintó S. Synaptic components are required for glioblastoma progression in Drosophila. PLoS Genet. 2022 Jul 25;18(7):e1010329. doi: 10.1371/journal.pgen.1010329. PMID: 35877760; PMCID: PMC9352205.
PUBMED DOIAlignment between glioblastoma internal clock and environmental cues ameliorates survival in Drosophila
Jarabo P, Barredo CG, de Pablo C, Casas-Tinto S, Martin FA. Alignment between glioblastoma internal clock and environmental cues ameliorates survival in Drosophila. Commun Biol. 2022 Jun 30;5(1):644. doi: 10.1038/s42003-022-03600-9. PMID: 35773327; PMCID: PMC9247055.
PUBMED DOIMechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP. (2022) Nature Communications.
García-García M, Sánchez-Perales S, Casas-Tintó S, Görlich D, Echarri A and del Pozo MA. Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP. (2022) Nature Communications. doi: 10.1038/s41467-022-28693-y. PMID: 35246520
PUBMED DOIMeeting report of the 17th Spanish Society for Developmental Biology Meeting (SEBD2020). (2021) Int J Dev Biol.
Araújo SJ, Almudi I, Bozal-Basterra L, Casares F, Casas-Tintó S, Escalante A, García-Moreno F, Losada-Pérez M, Maeso I, Marcon L, Ocaña O, Pampliega O, Rada-Iglesias Á, Rayon T, Sharpe J, Sutherland JD, Villa Del Campo C, Barrio R.
PUBMED DOILiver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease
1. Gómez-Mariano G, Matamala N, Martínez S, Justo I, Marcacuzco A, Jiménez C, Monzón S, Cuesta I, Garfia C, Martínez MT, Huch M, Pérez de Castro I, Posada M, Janciauskiene S, Martínez-Delgado B. Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease. Hepatol Int. 2019;14: 127-137.
DOIThe EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas
2. Segura-Collar B, Gargini R, Tovar-Ambel E, Hérnandez-SanMiguel E, Epifano C, Pérez de Castro I, Hernández-Lain A, Casas-Tintó S, Sánchez-Gómez P. The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas. Cancers (Basel). 2020;12(1):208.
DOIConsequences of Lmna Exon 4 Mutations in Myoblast Function
3. Gómez-Domínguez, D.; Epifano, C.; de Miguel, F.; Castaño, A.G.; Vilaplana-Martí, B.; Martín, A.; Amarilla-Quintana, S.; Bertrand, A.T.; Bonne, G.; Ramón-Azcón, J.; Rodríguez-Milla, M.A.; Pérez de Castro, I. Consequences of Lmna Exon 4 Mutations in Myoblast Function. Cells 2020, 9, 1286.
DOIMitochondrial RNA methyltransferase TRMT61B is a new, potential aneuploidy biomarker and therapeutic target for unstable cancers
4. Martín A, Vilaplana-Martí B, Macías RIR, Martínez-Ramírez A, Cerezo A, Cabezas-Sainz P, Garranzo Asensio M, Epifano C, Amarilla S, Gómez-Domínguez D, Hernández I, Caleiras E, Camps J, Barderas R, Sánchez L, Velasco S, Pérez de Castro I. Mitochondrial RNA methyltransferase TRMT61B is a new, potential aneuploidy biomarker and therapeutic target for unstable cancers. Cell Death and Differentiation, 2022, 30(1): 37-53
DOIOpen label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors.The GREKO (GRanulosa Et KetOconazole) trial. GETHI 2011-03
5. García-Donas J, Hurtado A, Garrigos L, Santaballa A, Redondo A, Vidal L, Lainez N, Guerra E, Rodríguez V, Cueva J, Bover I, Palacio I, Rubio MJ, Prieto M, López-Guerrero JA, Rodríguez-Moreno JF, García-Casado Z, García-Martínez E, Taus A, Pérez de Castro I, Navarro P, Grande E. Open label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors.The GREKO (GRanulosa Et KetOconazole) trial. GETHI 2011-03. Clinical and Translational Oncology, 2023, 25: 2090-2098
DOICRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds
6. Amarilla-Quintana S, Navarro P, Ramos A, Montero-Calle A, Cabezas-Sainz P, Barrero MJ, Megias D, Vilaplana-Marti B, Epifano C, Gomez-Dominguez D, Hernandez I, Monzon S, Cuesta I, Sanchez L, Barderas R, Garcia-Donas J, Alberto Martin, Pérez de Castro I. CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds. Molecular Oncology 2025, 19: 1092-1116
DOICRISPR/Cas9-mediated elimination of the LMNA c.745C>G pathogenic mutation enhances survival and cardiac function in LMNA-associated congenital muscular dystrophy
7. Gómez-Domínguez D, Epifano C, Hernández I, Vilaplana-Martí B, Cesar S, de Molina-Iracheta A, Sena-Esteves M, Sarquella-Brugada G, Pérez de Castro I. CRISPR/Cas9-mediated elimination of the LMNA c.745C>G pathogenic mutation enhances survival and cardiac function in LMNA-associated congenital muscular dystrophy. bioRxiv 2025.02.13.638060; (in press in Molecular Therapy-Methods & Clinical Development)
DOIEUROPLAN: a project to support the development of national plans on rare diseases in Europe. Public Health Genomics. 2013;16(6):278-87
Taruscio D, Gentile AE, De Santis M, Ferrelli RM, Posada de la Paz M, Hens M, Huizer J, Fregonese L, Stefanov R, Bottarelli V, Weinman A, Le Cam Y, Gavhed D, Mincarone P, Bushby K, Frazzica RG, Donati C, Vittozzi L, Jessop E.
PUBMED DOIChildhood vasculitis hospitalizations in Spain, 1997-2011. Georgian Med News. 2014 May;(230):65-72
Villaverde-Hueso A, Alonso-Ferreira V, Morales-Piga A, Hens-Pérez M, Abaitua I, Posada de la Paz M.
PUBMEDRecord linkage between hospital discharges and mortality registries for motor neuron disease case ascertainment for the Spanish National Rare Diseases Registry. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Jun;15(3-4):275-8
Ruiz E, Ramalle-Gómara E, Quiñones C; SpainRDR Working Group
PUBMED DOIContent with Investigacion .
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Francisco Javier Alonso García de la Rosa
Profesor de Investigación de OPIs. Jefe de grupo
ORCID code: 0000-0002-6287-8391
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Saint Thomas Cervera Mayor
Investigador predoctoral
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Selene Martinez Rodriguez
Técnica superior laboratorio
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María Iranzo Martinez
Técnico especializado de OPIs
List of staff