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...

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Autores: Mateo, Francesca|||0000-0002-2342-7010, Arenas, Enrique J.|||0000-0001-7076-2666, Aguilar, Helena, Serra-Musach, Jordi, Ruiz de Garibay, Gorka|||0000-0001-9936-8419, Boni, Jacopo|||0000-0003-2626-9393, Maicas, Miren|||0000-0003-1404-5552, Du, Shisuo, Iorio, Francesco|||0000-0001-7063-8913, Herranz-Ors, Carmen|||0000-0002-2866-0321, Islam, Abul, Prado, X., Llorente, Alicia, Petit Montserrat, Anna|||0000-0002-9284-095X, Vidal, August|||0000-0001-5727-2099, Català, Isabel, Soler, Teresa, Venturas, G., Rojo-Sebastian, Alejandro|||0000-0001-6439-3518, Serra, Helena, Cuadras, Daniel|||0000-0001-8780-1764, Blanco Guillermo, Ignacio|||0000-0002-7414-7481, Lozano, José, Canals, Francesc|||0000-0002-0650-1135, Sieuwerts, Anieta M., De Weerd, Vanja, Look, Maxime P., Puertas, Sara, García, Nadia, Perkins, Archibald S., Bonifaci, Núria|||0000-0002-8193-6825, Skowron, Margaretha A., Gómez-Baldó, Laia, Hernández, Vanessa, Martínez-Aranda, Antonio, Martínez-Iniesta, Maria|||0000-0001-6252-6671, Serrat Farran, Xènia|||0000-0001-7611-5400, Cerón, Julián|||0000-0003-4739-2243, Brunet, Joan|||0000-0003-1945-3512, Barretina-Ginesta, Maria-Pilar|||0000-0003-0074-6614, Gil, Mercedes|||0000-0002-7387-2139, Falo, Catalina|||0000-0002-5714-6823, Fernández, Adela, Morilla, Idoia, Pernas, Sonia|||0000-0002-1485-5080, Plà, Maria Jesus, Andreu, Xavier, Seguí Palmer, Miguel Ángel|||0000-0002-5103-6746, Ballester, Rosa|||0000-0002-7870-4185, Castellà Fernández, Eva, Nellist, Mark D., Morales, Saleta, Valls, Joan|||0000-0002-4806-7568, Velasco Sánchez, Ana, Matías-Guiu, Xavier|||0000-0002-7201-6605, Figueras, Agnes, Sánchez-Mut, José Vicente|||0000-0002-9292-8521, Sánchez Céspedes, Montse|||0000-0002-6045-5627, Cordero Casanovas, Alex|||0000-0002-2224-7122, Gómez-Miragaya, Jorge|||0000-0003-1801-4681, Palomero, Luis|||0000-0002-9144-1017, Gomez-Caamaño, Antonio|||0000-0002-9773-4590, Gajewski, Thomas F., Cohen, Ezra E. W., Jesiotr, Marzena, Bodnar, Lubomir, Quintela-Fandino, Miguel|||0000-0003-1648-1964, Lopez-Bigas, Nuria|||0000-0003-4925-8988, Valdés-Mas, Rafael, Puente, Xose S.|||0000-0001-9525-1483, Viñals, Francesc|||0000-0002-9918-6751, Casanovas, Oriol|||0000-0002-4298-3995, Graupera, Mariona|||0000-0003-4608-4185, Hernandez-Losa, Javier|||0000-0003-1526-3201, Ramón y Cajal, Santiago|||0000-0002-3867-1390, Garcia-Alonso, Luz|||0000-0002-7863-9619, Saez-Rodriguez, J., Esteller, M.|||0000-0003-4490-6093, Sierra-Jimenez, Angels|||0000-0003-1023-3492, Martín-Martín, Natalia|||0000-0002-2527-429X, Matheu Fernandez, Ander, Carracedo, Arkaitz|||0000-0001-5957-1260, González-Suárez, Eva|||0000-0003-0858-8171, Nanjundan, Meera, Cortés Castán, Javier|||0000-0001-7623-1583, Lázaro García, Conxi|||0000-0002-7198-5906, Odero, Maria D.|||0000-0002-8858-2054, Martens, John W. M., Moreno-Bueno, Gema, Barcellos-Hoff, Mary Helen, Villanueva, Alejandro|||0000-0001-5164-0006, Gomis, Roger R.|||0000-0001-6473-2858, Pujana, Miguel Angel|||0000-0003-3222-4044
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:291146
Acceso en línea:https://ddd.uab.cat/record/291146
https://dx.doi.org/urn:doi:10.1038/onc.2016.427
Access Level:acceso abierto
Palabra clave:Adaptor Proteins, Signal Transducing
Adult
Aged
Breast Neoplasms
Carrier Proteins
Cell Proliferation
DNA-Binding Proteins
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
MCF-7 Cells
Microfilament Proteins
Middle Aged
Neoplasm Metastasis
Osteonectin
Proto-Oncogenes
Signal Transduction
SOX9 Transcription Factor
TOR Serine-Threonine Kinases
Transcription Factors
Xenograft Model Antitumor Assays
Descripción
Sumario: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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