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