Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition
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- dc.contributor.author Mateo, Francescaca
- dc.contributor.author López Bigas, Núriaca
- dc.contributor.author Pujana, Miguel Angelca
- dc.date.accessioned 2017-07-04T07:59:28Z
- dc.date.available 2017-07-04T07:59:28Z
- dc.date.issued 2017
- dc.description.abstract Inhibitors 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.description.sponsorship This study was supported by the following bodies and grants: the Scientific Foundation ‘Asociación Española Contra el Cáncer’ (AECC, Stable Coordinated Group, Hereditary Cancer); the BBVA Foundation; the Eugenio Rodríguez 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 Únicos’ 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.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Mateo F, Arenas EJ, Aguilar H, Serra-Musach J, Ruiz de Garibay G, Boni J, Maicas M et al. Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene. 2017; 36: 2737-2749. DOI: 10.1038/onc.2016.427
- dc.identifier.doi http://dx.doi.org/10.1038/onc.2016.427
- dc.identifier.issn 0950-9232
- dc.identifier.uri http://hdl.handle.net/10230/32499
- dc.language.iso eng
- dc.publisher Nature Publishing Groupca
- dc.relation.ispartof Oncogene. 2017; 36: 2737-2749
- dc.rights © Nature Publishing Group. http://dx.doi.org/10.1038/onc.2016.427. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
- dc.title Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibitionca
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion