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Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

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dc.contributor.authorMateo, F
dc.contributor.authorArenas, E J
dc.contributor.authorAguilar, H
dc.contributor.authorSerra-Musach, J
dc.contributor.authorde Garibay, G Ruiz
dc.contributor.authorBoni, J
dc.contributor.authorMaicas, M
dc.contributor.authorDu, S
dc.contributor.authorIorio, F
dc.contributor.authorHerranz-Ors, C
dc.contributor.authorIslam, A
dc.contributor.authorPrado, X
dc.contributor.authorLlorente, A
dc.contributor.authorPetit, A
dc.contributor.authorVidal, A
dc.contributor.authorCatalà, I
dc.contributor.authorSoler, T
dc.contributor.authorVenturas, G
dc.contributor.authorRojo-Sebastian, A
dc.contributor.authorSerra, H
dc.contributor.authorCuadras, D
dc.contributor.authorBlanco, I
dc.contributor.authorLozano, J
dc.contributor.authorCanals, F
dc.contributor.authorSieuwerts, A M
dc.contributor.authorde Weerd, V
dc.contributor.authorLook, M P
dc.contributor.authorPuertas, S
dc.contributor.authorGarcía, N
dc.contributor.authorPerkins, A S
dc.contributor.authorBonifaci, N
dc.contributor.authorSkowron, M
dc.contributor.authorGómez-Baldó, L
dc.contributor.authorHernández, V
dc.contributor.authorMartínez-Aranda, A
dc.contributor.authorMartínez-Iniesta, M
dc.contributor.authorSerrat, X
dc.contributor.authorCerón, J
dc.contributor.authorBrunet, J
dc.contributor.authorBarretina, M P
dc.contributor.authorGil, M
dc.contributor.authorFalo, C
dc.contributor.authorFernández, A
dc.contributor.authorMorilla, I
dc.contributor.authorPernas, S
dc.contributor.authorPlà, M J
dc.contributor.authorAndreu, X
dc.contributor.authorSeguí, M A
dc.contributor.authorBallester, R
dc.contributor.authorCastellà, E
dc.contributor.authorNellist, M
dc.contributor.authorMorales, S
dc.contributor.authorValls, J
dc.contributor.authorVelasco, A
dc.contributor.authorMatias-Guiu, X
dc.contributor.authorFigueras, A
dc.contributor.authorSánchez-Mut, J V
dc.contributor.authorSánchez-Céspedes, M
dc.contributor.authorCordero, A
dc.contributor.authorGómez-Miragaya, J
dc.contributor.authorPalomero, L
dc.contributor.authorGómez, A
dc.contributor.authorGajewski, T F
dc.contributor.authorCohen, E E W
dc.contributor.authorJesiotr, M
dc.contributor.authorBodnar, L
dc.contributor.authorQuintela-Fandino, M
dc.contributor.authorLópez-Bigas, N
dc.contributor.authorValdés-Mas, R
dc.contributor.authorPuente, X S
dc.contributor.authorViñals, F
dc.contributor.authorCasanovas, O
dc.contributor.authorGraupera, M
dc.contributor.authorHernández-Losa, J
dc.contributor.authorRamón Y Cajal, S
dc.contributor.authorGarcía-Alonso, L
dc.contributor.authorSaez-Rodriguez, J
dc.contributor.authorEsteller, M
dc.contributor.authorSierra, A
dc.contributor.authorMartín-Martín, N
dc.contributor.authorMatheu, A
dc.contributor.authorCarracedo, A
dc.contributor.authorGonzález-Suárez, E
dc.contributor.authorNanjundan, M
dc.contributor.authorCortés, J
dc.contributor.authorLázaro, C
dc.contributor.authorOdero, M D
dc.contributor.authorMartens, J W M
dc.contributor.authorMoreno-Bueno, G
dc.contributor.authorBarcellos-Hoff, M H
dc.contributor.authorVillanueva, A
dc.contributor.authorGomis, R R
dc.contributor.authorPujana, M A
dc.contributor.funderFundación BBVA
dc.contributor.funderAsociación Española Contra el Cáncer
dc.contributor.funderGovernment of Catalonia (España)
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderMinisterio de Ciencia e Innovación (España)
dc.contributor.funderFundación La Caixa
dc.date.accessioned2024-10-22T09:58:35Z
dc.date.available2024-10-22T09:58:35Z
dc.date.issued2017-05-11
dc.descriptionWe thank Ander Urruticoechea, Gabriel Capella and George Thomas for helpful discussion; Ana Isabel Extremera, Antoni Xaubet and Julio Ancochea for administrative support; and Sebastien Tosi from the Advanced Digital Microscopy Facility at IRB Barcelona for image analysis. We also thank Xiyun Deng, Yanna Cao, Tien C Ko, Yi Zhang (The University of Texas Health Science Centre at Houston) and Adrian W Moore (RIKEN Brain Science Institute) for their support in evaluating antibodies against EVI1. This study was supported by the following bodies and grants: the Scientific Foundation 'Asociacion Espanola Contra el Cancer' (AECC, Stable Coordinated Group, Hereditary Cancer); the BBVA Foundation; the Eugenio Rodriguez Pascual Foundation grant 2012; Generalitat de Catalunya AGAUR SGR 2012 grants 283, 290 and 312, and SGR 2014 grants 364, 530, and 535; Spanish Ministry of Health ISCIII FIS grants PI10/00057, PI10/00222, PI10/01422, PI12/01528, PI13/00132, and PI14/00336. ISCIII RTICC grants RD06/0020/1051, RD12/0036/0007, RD12/0036/0008 and RD12/0036/0063; Spanish Ministry of Science and Innovation, 'Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa', MINECO grants SAF2010-20203 and SAF2013-46196; and the Telemaraton 2014 'Todos Somos Raros, Todos Somos Unicos' grant P35. EJA was supported by 'la Caixa' PhD fellowship program, F Iorio was supported by a fellowship from the EMBL-EBI and the Wellcome Trust Sanger Institute Postdoctoral (ESPOD) program, and NL-B, ME and RRG were supported by ICREA. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, either in the submission form or the text of the manuscript.
dc.description.abstractInhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.
dc.identifier.pmchttps://pmc.ncbi.nlm.nih.gov/articles/PMC5442428/
dc.identifier.pubmedID27991928
dc.identifier.urihttps://hdl.handle.net/20.500.12105/25194
dc.language.isoeng
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2013-46196-R/ES/MECANISMOS DE LATENCIA METASTATICA EN CANCER DE MAMA/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MICINN//SAF2010-20203/ES/PAPEL DE KSR EN LA MODULACION DE LAS SEÑALES ONCOGENICAS DEPENDIENTES DE RAS/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//RD12%2F0036%2F0063/ES/Cáncer/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//RD12%2F0036%2F0008/ES/Cáncer/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MSC//RD06%2F0020%2F1051/ES/RED TEMÁTICA DE INVESTIGACIÓN COOPERATIVA DEL CANCER/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI14%2F00336/ES/Prevención y tratamiento personalizado de la metástasis cerebral: desarrollo de nuevas terapias basadas en biomarcadores diana de predicción y prognosis (PETRABRAINMET)/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI13%2F00132/ES/Implicación de Gasdermina B (GSDMB) en progresión tumoral y comportamiento clínico de tumores HER2+/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI12%2F01528/ES/ESTUDIO INTEGRADO DEL CÁNCER DE MAMA TRIPLE-NEGATIVO/
dc.relation.projectIDP
dc.repisalud.institucionCNIO
dc.rights.accessRightsopen access
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBREAST-CANCER
dc.subjectMAMMARY STEM
dc.subjectMESENCHYMAL TRANSITION
dc.subjectEMBRYONIC STEM
dc.subjectSELF-RENEWAL
dc.subjectEXPRESSION
dc.subjectGENES
dc.subjectPATHWAY
dc.subjectTARGET
dc.subjectMOUSE
dc.titleStem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.
dc.typeresearch article
dspace.entity.typePublication
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