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

2016; Springer Nature; Volume: 36; Issue: 19 Linguagem: Inglês

10.1038/onc.2016.427

1476-5594

Francesca Mateo, Enrique J. Arenas, H. Aguilar, Jordi Serra-Musach, Gorka Ruíz de Garibay, Jacopo Boni, Miren Maicas, Shisuo Du, Francesco Iorio, Carmen Herranz, Abul Bashar Mir Md. Khademul Islam, X Prado, Alicia Llorente Lope, Ana Petit, August Vidal, I. Català, T Soler, G Venturas, Alejandro Rojo‐Sebastián, Helena Serra, Daniel Cuadras, Ignacio Blanco, José Lozano, Françesc Canals, Anieta M. Sieuwerts, Vanja de Weerd, Maxime P. Look, Sara Puertas, N. García, Archibald S. Perkins, Núria Bonifaci, Margaretha A. Skowron, Laia Gómez‐Baldó, Vanessa Hernández, Antonio Martínez-Aranda, María Martínez‐Iniesta, Xènia Serrat, Julián Cerón, Joan Brunet, M P Barretina, Miguel Ángel Cobos Gil, Catalina Falo, Adela Fernández, Idoia Morilla, Sònia Pernas, M.J. Plà, Xavier Andreu, Miguel Ángel Seguí, R. Ballester, E. Castellà, Mark Nellist, Serafín Morales, Joan Valls, Ana Velasco, Xavier Matías‐Guiu, António Figueras, José V. Sánchez‐Mut, Montse Sánchez‐Céspedes, Álex Cordero, Jorge Gómez‐Miragaya, Luís Palomero, Antonio Gómez, Thomas F. Gajewski, Ezra E.W. Cohen, M Jesiotr, Lubomir Bodnar, Miguel Quintela‐Fandino, Núria López-Bigas, Rafael Valdés‐Mas, Xosé S. Puente, Francesc Viñals, Oriol Casanovas, Mariona Graupera, Javier Hernández‐Losa, Santiago Ramón y Cajal, Luz García‐Alonso, Julio Sáez-Rodríguez, Manel Esteller, Àngels Sierra, Natalia Martín-Martín, Ander Matheu, Arkaitz Carracedo, Eva González‐Suárez, Meera Nanjundan, Javier Cortés, Conxi Lázaro, María D. Odero, John W.M. Martens, Gema Moreno‐Bueno, Mary Helen Barcellos‐Hoff, Alberto Villanueva, Roger R. Gomis, Miguel Ángel Pujana,

Cancer Cells and Metastasis

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.