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

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

Oncogene (2016-12-20)

F Mateo, E J Arenas, H Aguilar, J Serra-Musach, G Ruiz de Garibay, J Boni, M Maicas, S Du, F Iorio, C Herranz-Ors, A Islam, X Prado, A Llorente, A Petit, A Vidal, I Català, T Soler, G Venturas, A Rojo-Sebastian, H Serra, D Cuadras, I Blanco, J Lozano, F Canals, A M Sieuwerts, V de Weerd, M P Look, S Puertas, N García, A S Perkins, N Bonifaci, M Skowron, L Gómez-Baldó, V Hernández, A Martínez-Aranda, M Martínez-Iniesta, X Serrat, J Cerón, J Brunet, M P Barretina, M Gil, C Falo, A Fernández, I Morilla, S Pernas, M J Plà, X Andreu, M A Seguí, R Ballester, E Castellà, M Nellist, S Morales, J Valls, A Velasco, X Matias-Guiu, A Figueras, J V Sánchez-Mut, M Sánchez-Céspedes, A Cordero, J Gómez-Miragaya, L Palomero, A Gómez, T F Gajewski, E E W Cohen, M Jesiotr, L Bodnar, M Quintela-Fandino, N López-Bigas, R Valdés-Mas, X S Puente, F Viñals, O Casanovas, M Graupera, J Hernández-Losa, S Ramón Y Cajal, L García-Alonso, J Saez-Rodriguez, M Esteller, A Sierra, N Martín-Martín, A Matheu, A Carracedo, E González-Suárez, M Nanjundan, J Cortés, C Lázaro, M D Odero, J W M Martens, G Moreno-Bueno, M H Barcellos-Hoff, A Villanueva, R R Gomis, M A Pujana

PMID27991928

RÉSUMÉ

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.

MATÉRIAUX

Référence du produit

Marque

Description du produit

V9131

Sigma-Aldrich

Anticorps monoclonal anti-vinculine antibody produced in mouse, clone hVIN-1, ascites fluid

EHU090781

Sigma-Aldrich

MISSION^® esiRNA, targeting human MECOM (1)