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

Francesca Mateo; E.J. Arenas; Helena Aguilar; Jordi Serra-Musach; Gorka Ruiz de Garibay; Jacopo Boni; M. Maicas; S. Du; F. Iorio; Carmen Herranz-Ors; A. Islam; X. Prado; A. Llorente; Anna Petit Montserrat; August Vidal; Isabel Català; Teresa Soler; G. Venturas; A. Rojo-Sebastian; H. Serra; Daniel Cuadras; I. Blanco; J. Lozano; Francesc Canals; A.M. Sieuwerts; V. De Weerd; M.P. Look; Sara Puertas; N. García; A.S. Perkins; Nuria Bonifaci; M. Skowron; Laia Gómez-Baldó; V. Hernández; Antonio Martínez-Aranda; Maria Martínez-Iniesta; Xènia Serrat Farran; Julián Cerón; J. Brunet; M.P. Barretina; Mercedes Gil; Catalina Falo; A. Fernández; I. Morilla; Sonia Pernas; M.J. Plà; Xavier Andreu; Miquel Angel Segui Palmer; Rosa Ballester; Eva Castellà Fernández; M. Nellist; S. Morales; J. Valls; A. Velasco; X. Matias-Guiu; Agnes Figueras; José Vicente Sánchez-Mut; Montse Sanchez-Cespedes; Alex Cordero Casanovas; Jorge Gómez-Miragaya; Luis Palomero; A.  Gómez; T.F. Gajewski; E.E.W. Cohen; M. Jesiotr; L. Bodnar; M. Quintela-Fandino; N. López-Bigas; Rafael Valdés-Mas; X.S. Puente; Francesc Viñals; O. Casanovas; M. Graupera; Javier Hernandez-Losa; Santiago Ramón y Cajal; L. García-Alonso; J. Saez-Rodriguez; M. Esteller; A. Sierra; N. Martín-Martín; A. Matheu; A. Carracedo; Eva González-Suárez; M. Nanjundan; Javier Cortés; Conxi Lazaro Garcia; M.D. Odero; J.W.M. Martens; G. Moreno-Bueno; M.H. Barcellos-Hoff; Alberto Villanueva; R.R. Gomis; Miguel Ángel Genestar Pujana

doi:10.1038/onc.2016.427

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

Francesca Mateo, E.J. Arenas, Helena Aguilar, Jordi Serra-Musach, Gorka Ruiz de Garibay, Jacopo Boni, M. Maicas, S. Du, F. Iorio, Carmen Herranz-Ors, A. Islam, X. Prado, A. Llorente, Anna Petit Montserrat, August Vidal, Isabel Català, Teresa Soler, G. Venturas, A. Rojo-Sebastian, H. SerraDaniel Cuadras, I. Blanco, J. Lozano, Francesc Canals, A.M. Sieuwerts, V. De Weerd, M.P. Look, Sara Puertas, N. García, A.S. Perkins, Nuria Bonifaci, M. Skowron, Laia Gómez-Baldó, V. Hernández, Antonio Martínez-Aranda, Maria Martínez-Iniesta, Xènia Serrat Farran, Julián Cerón, J. Brunet, M.P. Barretina, Mercedes Gil, Catalina Falo, A. Fernández, I. Morilla, Sonia Pernas, M.J. Plà, Xavier Andreu, Miquel Angel Segui Palmer, Rosa Ballester, Eva Castellà Fernández, M. Nellist, S. Morales, J. Valls, A. Velasco, X. Matias-Guiu, Agnes Figueras, José Vicente Sánchez-Mut, Montse Sanchez-Cespedes, Alex Cordero Casanovas, Jorge Gómez-Miragaya, Luis Palomero, A. Gómez, T.F. Gajewski, E.E.W. Cohen, M. Jesiotr, L. Bodnar, M. Quintela-Fandino, N. López-Bigas, Rafael Valdés-Mas, X.S. Puente, Francesc Viñals, O. Casanovas, M. Graupera, Javier Hernandez-Losa, Santiago Ramón y Cajal, L. García-Alonso, J. Saez-Rodriguez, M. Esteller, A. Sierra, N. Martín-Martín, A. Matheu, A. Carracedo, Eva González-Suárez, M. Nanjundan, Javier Cortés, Conxi Lazaro Garcia, M.D. Odero, J.W.M. Martens, G. Moreno-Bueno, M.H. Barcellos-Hoff, Alberto Villanueva, R.R. Gomis, Miguel Ángel Genestar Pujana

Departament de Ciències Morfològiques

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33 Cites (Scopus)

Resum

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.

Idioma original	Anglès
Pàgines (de-a)	2737-2749
Nombre de pàgines	13
Revista	Oncogene
Volum	36
Número	19
DOIs	https://doi.org/10.1038/onc.2016.427
Estat de la publicació	Publicada - 2017

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10.1038/onc.2016.427

https://ddd.uab.cat/record/291146

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Mateo, F., Arenas, E. J., Aguilar, H., Serra-Musach, J., Ruiz de Garibay, G., Boni, J., Maicas, M., Du, S., Iorio, F., Herranz-Ors, C., Islam, A., Prado, X., Llorente, A., Petit Montserrat, A., Vidal, A., Català, I., Soler, T., Venturas, G., Rojo-Sebastian, A., ... Genestar Pujana, M. Á. (2017). Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene, 36(19), 2737-2749. https://doi.org/10.1038/onc.2016.427

@article{46ea049c8279404e8fc228858f70549a,

title = "Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition",

abstract = "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.",

keywords = "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",

author = "Francesca Mateo and E.J. Arenas and Helena Aguilar and Jordi Serra-Musach and \{Ruiz de Garibay\}, Gorka and Jacopo Boni and M. Maicas and S. Du and F. Iorio and Carmen Herranz-Ors and A. Islam and X. Prado and A. Llorente and \{Petit Montserrat\}, Anna and August Vidal and Isabel Catal{\`a} and Teresa Soler and G. Venturas and A. Rojo-Sebastian and H. Serra and Daniel Cuadras and I. Blanco and J. Lozano and Francesc Canals and A.M. Sieuwerts and \{De Weerd\}, V. and M.P. Look and Sara Puertas and N. Garc{\'i}a and A.S. Perkins and Nuria Bonifaci and M. Skowron and Laia G{\'o}mez-Bald{\'o} and V. Hern{\'a}ndez and Antonio Mart{\'i}nez-Aranda and Maria Mart{\'i}nez-Iniesta and \{Serrat Farran\}, X{\`e}nia and Juli{\'a}n Cer{\'o}n and J. Brunet and M.P. Barretina and Mercedes Gil and Catalina Falo and A. Fern{\'a}ndez and I. Morilla and Sonia Pernas and M.J. Pl{\`a} and Xavier Andreu and \{Segui Palmer\}, \{Miquel Angel\} and Rosa Ballester and \{Castell{\`a} Fern{\'a}ndez\}, Eva and M. Nellist and S. Morales and J. Valls and A. Velasco and X. Matias-Guiu and Agnes Figueras and S{\'a}nchez-Mut, \{Jos{\'e} Vicente\} and Montse Sanchez-Cespedes and \{Cordero Casanovas\}, Alex and Jorge G{\'o}mez-Miragaya and Luis Palomero and A. G{\'o}mez and T.F. Gajewski and E.E.W. Cohen and M. Jesiotr and L. Bodnar and M. Quintela-Fandino and N. L{\'o}pez-Bigas and Rafael Vald{\'e}s-Mas and X.S. Puente and Francesc Vi{\~n}als and O. Casanovas and M. Graupera and Javier Hernandez-Losa and \{Ram{\'o}n y Cajal\}, Santiago and L. Garc{\'i}a-Alonso and J. Saez-Rodriguez and M. Esteller and A. Sierra and N. Mart{\'i}n-Mart{\'i}n and A. Matheu and A. Carracedo and Eva Gonz{\'a}lez-Su{\'a}rez and M. Nanjundan and Javier Cort{\'e}s and \{Lazaro Garcia\}, Conxi and M.D. Odero and J.W.M. Martens and G. Moreno-Bueno and M.H. Barcellos-Hoff and Alberto Villanueva and R.R. Gomis and \{Genestar Pujana\}, \{Miguel {\'A}ngel\}",

year = "2017",

doi = "10.1038/onc.2016.427",

language = "English",

volume = "36",

pages = "2737--2749",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer Nature",

number = "19",

}

Mateo, F, Arenas, EJ, Aguilar, H, Serra-Musach, J, Ruiz de Garibay, G, Boni, J, Maicas, M, Du, S, Iorio, F, Herranz-Ors, C, Islam, A, Prado, X, Llorente, A, Petit Montserrat, A, Vidal, A, Català, I, Soler, T, Venturas, G, Rojo-Sebastian, A, Serra, H, Cuadras, D, Blanco, I, Lozano, J, Canals, F, Sieuwerts, AM, De Weerd, V, Look, MP, Puertas, S, García, N, Perkins, AS, Bonifaci, N, Skowron, M, Gómez-Baldó, L, Hernández, V, Martínez-Aranda, A, Martínez-Iniesta, M, Serrat Farran, X, Cerón, J, Brunet, J, Barretina, MP, Gil, M, Falo, C, Fernández, A, Morilla, I, Pernas, S, Plà, MJ, Andreu, X, Segui Palmer, MA, Ballester, R, Castellà Fernández, E, Nellist, M, Morales, S, Valls, J, Velasco, A, Matias-Guiu, X, Figueras, A, Sánchez-Mut, JV, Sanchez-Cespedes, M, Cordero Casanovas, A, Gómez-Miragaya, J, Palomero, L, Gómez, A, Gajewski, TF, Cohen, EEW, Jesiotr, M, Bodnar, L, Quintela-Fandino, M, López-Bigas, N, Valdés-Mas, R, Puente, XS, Viñals, F, Casanovas, O, Graupera, M, Hernandez-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, Lazaro Garcia, C, Odero, MD, Martens, JWM, Moreno-Bueno, G, Barcellos-Hoff, MH, Villanueva, A, Gomis, RR & Genestar Pujana, MÁ 2017, 'Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition', Oncogene, vol. 36, núm. 19, pàg. 2737-2749. https://doi.org/10.1038/onc.2016.427

TY - JOUR

T1 - Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

AU - Mateo, Francesca

AU - Arenas, E.J.

AU - Aguilar, Helena

AU - Serra-Musach, Jordi

AU - Ruiz de Garibay, Gorka

AU - Boni, Jacopo

AU - Maicas, M.

AU - Du, S.

AU - Iorio, F.

AU - Herranz-Ors, Carmen

AU - Islam, A.

AU - Prado, X.

AU - Llorente, A.

AU - Petit Montserrat, Anna

AU - Vidal, August

AU - Català, Isabel

AU - Soler, Teresa

AU - Venturas, G.

AU - Rojo-Sebastian, A.

AU - Serra, H.

AU - Cuadras, Daniel

AU - Blanco, I.

AU - Lozano, J.

AU - Canals, Francesc

AU - Sieuwerts, A.M.

AU - De Weerd, V.

AU - Look, M.P.

AU - Puertas, Sara

AU - García, N.

AU - Perkins, A.S.

AU - Bonifaci, Nuria

AU - Skowron, M.

AU - Gómez-Baldó, Laia

AU - Hernández, V.

AU - Martínez-Aranda, Antonio

AU - Martínez-Iniesta, Maria

AU - Serrat Farran, Xènia

AU - Cerón, Julián

AU - Brunet, J.

AU - Barretina, M.P.

AU - Gil, Mercedes

AU - Falo, Catalina

AU - Fernández, A.

AU - Morilla, I.

AU - Pernas, Sonia

AU - Plà, M.J.

AU - Andreu, Xavier

AU - Segui Palmer, Miquel Angel

AU - Ballester, Rosa

AU - Castellà Fernández, Eva

AU - Nellist, M.

AU - Morales, S.

AU - Valls, J.

AU - Velasco, A.

AU - Matias-Guiu, X.

AU - Figueras, Agnes

AU - Sánchez-Mut, José Vicente

AU - Sanchez-Cespedes, Montse

AU - Cordero Casanovas, Alex

AU - Gómez-Miragaya, Jorge

AU - Palomero, Luis

AU - Gómez, A.

AU - Gajewski, T.F.

AU - Cohen, E.E.W.

AU - Jesiotr, M.

AU - Bodnar, L.

AU - Quintela-Fandino, M.

AU - López-Bigas, N.

AU - Valdés-Mas, Rafael

AU - Puente, X.S.

AU - Viñals, Francesc

AU - Casanovas, O.

AU - Graupera, M.

AU - Hernandez-Losa, Javier

AU - Ramón y Cajal, Santiago

AU - García-Alonso, L.

AU - Saez-Rodriguez, J.

AU - Esteller, M.

AU - Sierra, A.

AU - Martín-Martín, N.

AU - Matheu, A.

AU - Carracedo, A.

AU - González-Suárez, Eva

AU - Nanjundan, M.

AU - Cortés, Javier

AU - Lazaro Garcia, Conxi

AU - Odero, M.D.

AU - Martens, J.W.M.

AU - Moreno-Bueno, G.

AU - Barcellos-Hoff, M.H.

AU - Villanueva, Alberto

AU - Gomis, R.R.

AU - Genestar Pujana, Miguel Ángel

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Adult

KW - Aged

KW - Breast Neoplasms

KW - Carrier Proteins

KW - Cell Proliferation

KW - DNA-Binding Proteins

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lung Neoplasms

KW - MCF-7 Cells

KW - Microfilament Proteins

KW - Middle Aged

KW - Neoplasm Metastasis

KW - Osteonectin

KW - Proto-Oncogenes

KW - Signal Transduction

KW - SOX9 Transcription Factor

KW - TOR Serine-Threonine Kinases

KW - Transcription Factors

KW - Xenograft Model Antitumor Assays

UR - https://www.scopus.com/pages/publications/85006511955

U2 - 10.1038/onc.2016.427

DO - 10.1038/onc.2016.427

M3 - Article

C2 - 27991928

SN - 0950-9232

VL - 36

SP - 2737

EP - 2749

JO - Oncogene

JF - Oncogene

IS - 19

ER -

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

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