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

• Published in: Oncogene Vol. 36; no. 19; pp. 2737 - 2749
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-05-2017; Nature Publishing Group
• Subjects: 38/39; 45/100; 45/15; 59/5; 631/67/1059/2326; 631/67/71; 64/60; 96/95; Adaptor Proteins, Signal Transducing - genetics; Adult; Aged; Apoptosis; Biochemistry; Biomedical research; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer cells; Cancer metastasis; Carrier Proteins - genetics; Cell Biology; Cell Proliferation - genetics; Consortia; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetics; Genomes; Health aspects; Hospitals; Human Genetics; Humans; Internal Medicine; Laboratories; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - secondary; MCF-7 Cells; MDS1 and EVI1 Complex Locus Protein; Medical research; Medicine; Medicine & Public Health; Metastasis; Microfilament Proteins - genetics; Middle Aged; Molecular biology; Neoplasm Metastasis; Oncology; Original; original-article; Osteonectin - genetics; Pathology; Phosphotransferases; Proto-Oncogenes - genetics; Radiation; Regulatory-Associated Protein of mTOR; Research centers; Research parks; Risk factors; Science; Signal Transduction - genetics; SOX9 Transcription Factor - genetics; Stem cells; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; Transcription Factors - genetics; Xenograft Model Antitumor Assays; New York; Netherlands; United Kingdom > UK; United States > US; Poland; Madrid Spain; Spain
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2016.427

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.