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Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition
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 model...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group
2017
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442428/ https://www.ncbi.nlm.nih.gov/pubmed/27991928 http://dx.doi.org/10.1038/onc.2016.427 |
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| author | Mateo, F Arenas, E J Aguilar, H Serra-Musach, J de Garibay, G Ruiz Boni, J Maicas, M Du, S Iorio, F Herranz-Ors, C Islam, A Prado, X Llorente, A Petit, A Vidal, A Català, I Soler, T Venturas, G Rojo-Sebastian, A Serra, H Cuadras, D Blanco, I Lozano, J Canals, F Sieuwerts, A M de Weerd, V Look, M P Puertas, S García, N Perkins, A S Bonifaci, N Skowron, M Gómez-Baldó, L Hernández, V Martínez-Aranda, A Martínez-Iniesta, M Serrat, X Cerón, J Brunet, J Barretina, M P Gil, M Falo, C Fernández, A Morilla, I Pernas, S Plà, M J Andreu, X Seguí, M A Ballester, R Castellà, E Nellist, M Morales, S Valls, J Velasco, A Matias-Guiu, X Figueras, A Sánchez-Mut, J V Sánchez-Céspedes, M Cordero, A Gómez-Miragaya, J Palomero, L Gómez, A Gajewski, T F Cohen, E E W Jesiotr, M Bodnar, L Quintela-Fandino, M López-Bigas, N Valdés-Mas, R Puente, X S Viñals, F Casanovas, O Graupera, M Hernández-Losa, J Ramón y Cajal, S García-Alonso, L Saez-Rodriguez, J Esteller, M Sierra, A Martín-Martín, N Matheu, A Carracedo, A González-Suárez, E Nanjundan, M Cortés, J Lázaro, C Odero, M D Martens, J W M Moreno-Bueno, G Barcellos-Hoff, M H Villanueva, A Gomis, R R Pujana, M A |
| author_facet | Mateo, F Arenas, E J Aguilar, H Serra-Musach, J de Garibay, G Ruiz Boni, J Maicas, M Du, S Iorio, F Herranz-Ors, C Islam, A Prado, X Llorente, A Petit, A Vidal, A Català, I Soler, T Venturas, G Rojo-Sebastian, A Serra, H Cuadras, D Blanco, I Lozano, J Canals, F Sieuwerts, A M de Weerd, V Look, M P Puertas, S García, N Perkins, A S Bonifaci, N Skowron, M Gómez-Baldó, L Hernández, V Martínez-Aranda, A Martínez-Iniesta, M Serrat, X Cerón, J Brunet, J Barretina, M P Gil, M Falo, C Fernández, A Morilla, I Pernas, S Plà, M J Andreu, X Seguí, M A Ballester, R Castellà, E Nellist, M Morales, S Valls, J Velasco, A Matias-Guiu, X Figueras, A Sánchez-Mut, J V Sánchez-Céspedes, M Cordero, A Gómez-Miragaya, J Palomero, L Gómez, A Gajewski, T F Cohen, E E W Jesiotr, M Bodnar, L Quintela-Fandino, M López-Bigas, N Valdés-Mas, R Puente, X S Viñals, F Casanovas, O Graupera, M Hernández-Losa, J Ramón y Cajal, S García-Alonso, L Saez-Rodriguez, J Esteller, M Sierra, A Martín-Martín, N Matheu, A Carracedo, A González-Suárez, E Nanjundan, M Cortés, J Lázaro, C Odero, M D Martens, J W M Moreno-Bueno, G Barcellos-Hoff, M H Villanueva, A Gomis, R R Pujana, M A |
| author_sort | Mateo, F |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-5442428 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-54424282017-06-02 Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition Mateo, F Arenas, E J Aguilar, H Serra-Musach, J de Garibay, G Ruiz Boni, J Maicas, M Du, S Iorio, F Herranz-Ors, C Islam, A Prado, X Llorente, A Petit, A Vidal, A Català, I Soler, T Venturas, G Rojo-Sebastian, A Serra, H Cuadras, D Blanco, I Lozano, J Canals, F Sieuwerts, A M de Weerd, V Look, M P Puertas, S García, N Perkins, A S Bonifaci, N Skowron, M Gómez-Baldó, L Hernández, V Martínez-Aranda, A Martínez-Iniesta, M Serrat, X Cerón, J Brunet, J Barretina, M P Gil, M Falo, C Fernández, A Morilla, I Pernas, S Plà, M J Andreu, X Seguí, M A Ballester, R Castellà, E Nellist, M Morales, S Valls, J Velasco, A Matias-Guiu, X Figueras, A Sánchez-Mut, J V Sánchez-Céspedes, M Cordero, A Gómez-Miragaya, J Palomero, L Gómez, A Gajewski, T F Cohen, E E W Jesiotr, M Bodnar, L Quintela-Fandino, M López-Bigas, N Valdés-Mas, R Puente, X S Viñals, F Casanovas, O Graupera, M Hernández-Losa, J Ramón y Cajal, S García-Alonso, L Saez-Rodriguez, J Esteller, M Sierra, A Martín-Martín, N Matheu, A Carracedo, A González-Suárez, E Nanjundan, M Cortés, J Lázaro, C Odero, M D Martens, J W M Moreno-Bueno, G Barcellos-Hoff, M H Villanueva, A Gomis, R R Pujana, M A Oncogene Original Article 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. Nature Publishing Group 2017-05-11 2016-12-19 /pmc/articles/PMC5442428/ /pubmed/27991928 http://dx.doi.org/10.1038/onc.2016.427 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ 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/ |
| spellingShingle | Original Article Mateo, F Arenas, E J Aguilar, H Serra-Musach, J de Garibay, G Ruiz Boni, J Maicas, M Du, S Iorio, F Herranz-Ors, C Islam, A Prado, X Llorente, A Petit, A Vidal, A Català, I Soler, T Venturas, G Rojo-Sebastian, A Serra, H Cuadras, D Blanco, I Lozano, J Canals, F Sieuwerts, A M de Weerd, V Look, M P Puertas, S García, N Perkins, A S Bonifaci, N Skowron, M Gómez-Baldó, L Hernández, V Martínez-Aranda, A Martínez-Iniesta, M Serrat, X Cerón, J Brunet, J Barretina, M P Gil, M Falo, C Fernández, A Morilla, I Pernas, S Plà, M J Andreu, X Seguí, M A Ballester, R Castellà, E Nellist, M Morales, S Valls, J Velasco, A Matias-Guiu, X Figueras, A Sánchez-Mut, J V Sánchez-Céspedes, M Cordero, A Gómez-Miragaya, J Palomero, L Gómez, A Gajewski, T F Cohen, E E W Jesiotr, M Bodnar, L Quintela-Fandino, M López-Bigas, N Valdés-Mas, R Puente, X S Viñals, F Casanovas, O Graupera, M Hernández-Losa, J Ramón y Cajal, S García-Alonso, L Saez-Rodriguez, J Esteller, M Sierra, A Martín-Martín, N Matheu, A Carracedo, A González-Suárez, E Nanjundan, M Cortés, J Lázaro, C Odero, M D Martens, J W M Moreno-Bueno, G Barcellos-Hoff, M H Villanueva, A Gomis, R R Pujana, M A Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition |
| title | Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition |
| title_full | Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition |
| title_fullStr | Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition |
| title_full_unstemmed | Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition |
| title_short | Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition |
| title_sort | stem cell-like transcriptional reprogramming mediates metastatic resistance to mtor inhibition |
| topic | Original Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442428/ https://www.ncbi.nlm.nih.gov/pubmed/27991928 http://dx.doi.org/10.1038/onc.2016.427 |
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