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A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.

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dc.contributor.authorZhu, Lucía
dc.contributor.authorRetana, Diana
dc.contributor.authorGarcía-Gómez, Pedro
dc.contributor.authorÁlvaro-Espinosa, Laura
dc.contributor.authorPriego, Neibla
dc.contributor.authorMasmudi-Martín, Mariam
dc.contributor.authorYebra, Natalia
dc.contributor.authorMiarka, Lauritz
dc.contributor.authorHernández-Encinas, Elena
dc.contributor.authorBlanco-Aparicio, Carmen
dc.contributor.authorMartínez, Sonia
dc.contributor.authorSobrino, Cecilia
dc.contributor.authorAjenjo, Nuria
dc.contributor.authorArtiga, Maria-Jesus
dc.contributor.authorOrtega-Paino, Eva
dc.contributor.authorTorres-Ruiz, Raúl
dc.contributor.authorRodríguez-Perales, Sandra
dc.contributor.authorSoffietti, Riccardo
dc.contributor.authorBertero, Luca
dc.contributor.authorCassoni, Paola
dc.contributor.authorWeiss, Tobias
dc.contributor.authorMuñoz, Javier
dc.contributor.authorSepúlveda, Juan Manuel
dc.contributor.authorGonzález-León, Pedro
dc.contributor.authorJiménez-Roldán, Luis
dc.contributor.authorMoreno, Luis Miguel
dc.contributor.authorEsteban, Olga
dc.contributor.authorPérez-Núñez, Ángel
dc.contributor.authorHernández-Laín, Aurelio
dc.contributor.authorToldos, Oscar
dc.contributor.authorRuano, Yolanda
dc.contributor.authorAlcázar, Lucía
dc.contributor.authorBlasco, Guillermo
dc.contributor.authorFernández-Alén, José
dc.contributor.authorCaleiras, Eduardo
dc.contributor.authorLafarga, Miguel
dc.contributor.authorMegías, Diego
dc.contributor.authorGraña-Castro, Osvaldo
dc.contributor.authorNör, Carolina
dc.contributor.authorTaylor, Michael D
dc.contributor.authorYoung, Leonie S
dc.contributor.authorVarešlija, Damir
dc.contributor.authorCosgrove, Nicola
dc.contributor.authorCouch, Fergus J
dc.contributor.authorCussó, Lorena
dc.contributor.authorDesco, Manuel
dc.contributor.authorMouron, Silvana
dc.contributor.authorQuintela Fandino, Miguel Angel
dc.contributor.authorWeller, Michael
dc.contributor.authorPastor Fernandez, Joaquin
dc.contributor.authorValiente, Manuel
dc.contributor.authorZhu, Lucía
dc.contributor.authorRetana, Diana
dc.contributor.authorGarcía-Gómez, Pedro
dc.contributor.authorÁlvaro-Espinosa, Laura
dc.contributor.authorPriego, Neibla
dc.contributor.authorMasmudi-Martín, Mariam
dc.contributor.authorYebra, Natalia
dc.contributor.authorMiarka, Lauritz
dc.contributor.authorHernández-Encinas, Elena
dc.contributor.authorBlanco-Aparicio, Carmen
dc.contributor.authorMartínez, Sonia
dc.contributor.authorSobrino, Cecilia
dc.contributor.authorAjenjo, Nuria
dc.contributor.authorArtiga, Maria-Jesus
dc.contributor.authorOrtega-Paino, Eva
dc.contributor.authorTorres-Ruiz, Raúl
dc.contributor.authorRodríguez-Perales, Sandra
dc.contributor.authorSoffietti, Riccardo
dc.contributor.authorBertero, Luca
dc.contributor.authorCassoni, Paola
dc.contributor.authorWeiss, Tobias
dc.contributor.authorMuñoz, Javier
dc.contributor.authorSepúlveda, Juan Manuel
dc.contributor.authorGonzález-León, Pedro
dc.contributor.authorJiménez-Roldán, Luis
dc.contributor.authorMoreno, Luis Miguel
dc.contributor.authorEsteban, Olga
dc.contributor.authorPérez-Núñez, Ángel
dc.contributor.authorHernández-Laín, Aurelio
dc.contributor.authorToldos, Oscar
dc.contributor.authorRuano, Yolanda
dc.contributor.authorAlcázar, Lucía
dc.contributor.authorBlasco, Guillermo
dc.contributor.authorFernández-Alén, José
dc.contributor.authorCaleiras, Eduardo
dc.contributor.authorLafarga, Miguel
dc.contributor.authorMegías, Diego
dc.contributor.authorGraña-Castro, Osvaldo
dc.contributor.authorNör, Carolina
dc.contributor.authorTaylor, Michael D
dc.contributor.authorYoung, Leonie S
dc.contributor.authorVarešlija, Damir
dc.contributor.authorCosgrove, Nicola
dc.contributor.authorCouch, Fergus J
dc.contributor.authorCussó, Lorena
dc.contributor.authorDesco, Manuel
dc.contributor.authorMouron, Silvana
dc.contributor.authorWeller, Michael
dc.contributor.funderMinisterio de Ciencia e Innovación (España)
dc.contributor.funderFundación Fero
dc.contributor.funderFundacio La Marato de TV3
dc.contributor.funderNIHR - Bristol Biomedical Research Centre (Reino Unido)
dc.contributor.funderFundacion Ramon Areces
dc.contributor.funderWorldwide Cancer Research
dc.contributor.funderUnión Europea. Comisión Europea. H2020
dc.contributor.funderAsociación Española Contra el Cáncer
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderFundación La Caixa
dc.contributor.funderFundación ProCNIC
dc.date.accessioned2024-10-25T11:23:59Z
dc.date.available2024-10-25T11:23:59Z
dc.date.issued2022-03-07
dc.descriptionWe want to thank all members from the Brain Metastasis Group, F.X. Real, M. Malumbres, and M. Barbacid for critical discussion of the manuscript, the CNIO Core Facilities for their excellent assistance, Antonio Cebria and Javier Klett for their excellent assistance in drug-screening, Sonsoles Rodriguez-Aristegui for her excellent work with preparation of different compounds and Alexandra de Francisco, Yolanda Sierra, and Maria de la Jara Felipe for their excellent work with animal preparation and imaging protocols. We also thank J. Massague (MSKCC) for some of the BrM cell lines. This work was supported by MINECO (SAF2017-89643-R, SAF2014-57243-R, SAF2015-62547-ERC) (M.V.), Fundacion FERO (IX FERO Grant for Research in Oncology) (M.V.), Fundacio La Marato de TV3 (141) (M.V.), Melanoma Research Alliance (Bristol-Myers Squibb-Melanoma Research Alliance Young Investigator Award 2017 ()) (M.V.), Beug Foundation (Prize for Metastasis Research 2017) (M.V.), Fundacion Ramon Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545)) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), ERC CoG (864759) (M.V.), Sophien-Stiftung zur Forderung der klinischen Krebsforschung (T.W.), Promedica Stiftung (T.W.), Stiftung fur angewandte Krebsforschung (T.W.), Forschungskredit of the University of Zurich (FK-18-054) (T.W.), Betty and David Koetser Foundation for Brain Research (T.W.), Foundation for Applied Cancer Research in Zurich (T.W., M.W.), Comunidad de Madrid (S2017/BMD-3867 RENIM-CM and Y2018/NMT-4949 NanoLiver-CM) and European structural and investment funds (M.D.), ISCIII (PT20/00044) co-funded by FEDER "A way of making Europe" (M.D.), Ministero dell'Istruzione, dell'Universita e della Ricerca-MIUR, "Dipartimenti di Eccellenza 2018-2022", (D15D18000410001) (L.B. and P.C.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award/ with the generous support of Walk the Walk (2019AugSF1310) (D.V.), La Caixa-Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.), La Caixa International PhD Program Fellowship-Marie Sklodowska-Curie (LCF/BQ/DI17/11620028) (P.G-G), MINECO-Severo Ochoa PhD Fellowship (BES-2017-081995) (L.A-E.), AECC Postdoctoral Fellowship (POSTD19016PRIE) (N.P.), Boehringer Ingelheim Fonds MD fellowship (L.M.). The contribution of the Experimental Therapeutics Programme was supported by core funding from the Spanish National Cancer Research Center (CNIO). CNIO is supported by the ISCIII, the Ministerio de Ciencia e Innovacion, and is a Severo Ochoa Center of Excellence (SEV-2015-0510). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovacion and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). M.V. was named Ramon y Cajal Investigator (RYC-2013-13365) and is member of EMBO YIP (4053). The authors declare that they have no conflict of interest.
dc.description.abstractWe report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.
dc.description.peerreviewedSí
dc.format.number3
dc.format.pagee14552
dc.format.volume14
dc.identifier.citationEMBO Mol Med . 2022 Mar 7;14(3):e14552.
dc.identifier.journalEmbo Molecular Medicine
dc.identifier.pubmedID35174975
dc.identifier.urihttps://hdl.handle.net/20.500.12105/25299
dc.language.isoeng
dc.publisherWiley
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SEV-2015-0510/ES/CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SEV-2015-0505/ES/CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III/
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/828972/EU
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2015-62547-ERC/ES/DECONSTRUYENDO LA ENFERMEDAD METASTATICA EN EL CEREBRO/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2014-57243-R/ES/ANALISIS DEL PAPEL DE LOS ASTROCITOS REACTIVOS EN LA METASTASIS CEREBRAL/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89643-R/ES/BIOLOGIA DE LOS ASTROCITOS REACTIVOS STAT3+ EN LA METASTASIS CEREBRAL/
dc.relation.publisherversionhttp://www.10.15252/emmm.202114552
dc.repisalud.institucionCNIO
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Investigación Clínica de Cáncer de Mama
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Metástasis Cerebral
dc.rights.accessRightsopen access
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectdrug-screen
dc.subjectmetastasis
dc.subjectorganotypic cultures
dc.subjectpatient-derived
dc.subjectresistance
dc.titleA clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.
dc.typeresearch article
dc.type.hasVersionVoR
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