Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition
Por:
Mateo, F, Arenas, EJ, Aguilar, H, Serra-Musach, J, de Garibay, GR, Boni, J, Maicas, M, Du, S, Iorio, F, Herranz-Ors, C, Islam, A, Prado, X, Llorente, A, Petit, A, Vidal, A, Catala, 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, Garcia, N, Perkins, AS, Bonifaci, N, Skowron, M, Gomez-Baldo, L, Hernandez, V, Martinez-Aranda, A, Martinez-Iniesta, M, Serrat, X, Ceron, J, Brunet, J, Barretina, MP, Gil, M, Falo, C, Fernandez, A, Morilla, I, Pernas, S, Pla, MJ, Andreu, X, Segui, MA, Ballester, R, Castella, E, Nellist, M, Morales, S, Valls, J, Velasco, A, Matias-Guiu, X, Figueras, A, Sanchez-Mut, JV, Sanchez-Cespedes, M, Cordero, A, Gomez-Miragaya, J, Palomero, L, Gomez, A, Gajewski, TF, Cohen, EEW, Jesiotr, M, Bodnar, L, Quintela-Fandino, M, Lopez-Bigas, N, Valdes-Mas, R, Puente, XS, Vinals, F, Casanovas, O, Graupera, M, Hernandez-Losa, J, Cajal, SRY, Garcia-Alonso, L, Saez-Rodriguez, J, Esteller, M, Sierra, A, Martin-Martin, N, Matheu, A, Carracedo, A, Gonzalez-Suarez, E, Nanjundan, M, Cortes, J, Lazaro, C, Odero, MD, Martens, JWM, Moreno-Bueno, G, Barcellos-Hoff, MH, Villanueva, A, Gomis, RR and Pujana, MA
Publicada:
11 may 2017
Resumen:
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.
Filiaciones:
Mateo, F:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Arenas, EJ:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Oncol Program, Baldiri Reixac 10, Barcelona 08028, Spain
Aguilar, H:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Serra-Musach, J:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
de Garibay, GR:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Boni, J:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Maicas, M:
Univ Navarra, Ctr Appl Med Res CIMA, Pamplona, Spain
Univ Navarra, Dept Biochem & Genet, Pamplona, Spain
Du, S:
NYU, Sch Med, Dept Radiat Oncol, New York, NY 10003 USA
Iorio, F:
European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England
Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England
Herranz-Ors, C:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Islam, A:
Univ Dhaka, Dept Genet Engn & Biotechnol, Dhaka, Bangladesh
Prado, X:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Llorente, A:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Petit, A:
Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Barcelona, Spain
Vidal, A:
Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Barcelona, Spain
Catala, I:
Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Barcelona, Spain
Soler, T:
Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Barcelona, Spain
Venturas, G:
Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Barcelona, Spain
Rojo-Sebastian, A:
MD Anderson Canc Ctr, Dept Pathol, Madrid, Spain
Serra, H:
ICO, Angiogenesis Res Grp, ProCURE, IDIBELL, Barcelona, Spain
Cuadras, D:
IDIBELL, Stat Unit, Barcelona, Spain
Blanco, I:
IDIBELL, ICO, Hereditary Canc Programme, Barcelona, Spain
Lozano, J:
Univ Malaga, Dept Mol Biol & Biochem, Malaga, Spain
Univ Hosp Virgen de la Victoria, Mediterranean Inst Adv Biotechnol & Hlth Res IBIM, Mol Oncol Lab, Malaga, Spain
Canals, F:
Vall Hebron Univ, Vall Hebron Inst Oncol, ProteoRed Inst Salud Carlos 3, Prote Lab, Barcelona, Spain
Sieuwerts, AM:
Erasmus Univ, Med Ctr, Daniel den Hoed Canc Ctr, Canc Genom Ctr,Dept Med Oncol, Rotterdam, Netherlands
de Weerd, V:
Erasmus Univ, Med Ctr, Daniel den Hoed Canc Ctr, Canc Genom Ctr,Dept Med Oncol, Rotterdam, Netherlands
Look, MP:
Erasmus Univ, Med Ctr, Daniel den Hoed Canc Ctr, Canc Genom Ctr,Dept Med Oncol, Rotterdam, Netherlands
Puertas, S:
IDIBELL, ICO, Chemoresistance & Predict Factors Lab, ProCURE, Barcelona, Spain
Garcia, N:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Perkins, AS:
Univ Rochester, Med Ctr, Sch Med & Dent, Rochester, NY USA
Bonifaci, N:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Skowron, M:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Gomez-Baldo, L:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Hernandez, V:
IDIBELL, Biol Clues Invas & Metastat Phenotype Lab, Barcelona, Spain
Martinez-Aranda, A:
IDIBELL, Biol Clues Invas & Metastat Phenotype Lab, Barcelona, Spain
Martinez-Iniesta, M:
IDIBELL, ICO, Chemoresistance & Predict Factors Lab, ProCURE, Barcelona, Spain
Serrat, X:
IDIBELL, Canc & Human Mol Genet, Barcelona, Spain
Ceron, J:
IDIBELL, Canc & Human Mol Genet, Barcelona, Spain
Brunet, J:
Girona Biomed Res Inst IDIBGI, ICO, Hereditary Canc Programme, Girona, Spain
Barretina, MP:
IDIBGI, ICO, Dept Med Oncol, Girona, Spain
Gil, M:
IDIBELL, ICO, Dept Med Oncol, Barcelona, Spain
Falo, C:
IDIBELL, ICO, Dept Med Oncol, Barcelona, Spain
Fernandez, A:
IDIBELL, ICO, Dept Med Oncol, Barcelona, Spain
Morilla, I:
IDIBELL, ICO, Dept Med Oncol, Barcelona, Spain
Pernas, S:
IDIBELL, ICO, Dept Med Oncol, Barcelona, Spain
Pla, MJ:
Univ Hosp Bellvitge, IDIBELL, Dept Gynecol, Barcelona, Spain
Andreu, X:
Parc Tauli Hosp Consortium, Dept Pathol, Barcelona, Spain
Segui, MA:
Parc Tauli Hosp Consortium, Med Oncol Serv, Barcelona, Spain
:
Univ Hosp Germans Trias & Pujol, Germans Trias & Pujol Res Inst IGTP, ICO, Dept Radiat Oncol, Barcelona, Spain
Castella, E:
Univ Hosp Germans Trias & Pujol, IGTP, ICO, Dept Pathol, Barcelona, Spain
Nellist, M:
Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands
Valls, J:
Univ Lleida, Hosp Arnau de Vilanova, Biomed Res Inst Lleida IRB Lleida, Lleida, Spain
Velasco, A:
Univ Lleida, Hosp Arnau de Vilanova, Biomed Res Inst Lleida IRB Lleida, Lleida, Spain
Matias-Guiu, X:
Univ Lleida, Hosp Arnau de Vilanova, Biomed Res Inst Lleida IRB Lleida, Lleida, Spain
Figueras, A:
ICO, Angiogenesis Res Grp, ProCURE, IDIBELL, Barcelona, Spain
Sanchez-Mut, JV:
IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Spain
Sanchez-Cespedes, M:
IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Spain
Cordero, A:
IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Spain
Gomez-Miragaya, J:
IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Spain
Palomero, L:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Gajewski, TF:
Univ Chicago, Dept Pathol, Chicago, IL 60611 USA
Univ Chicago, Dept Med, Chicago, IL USA
Cohen, EEW:
Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92037 USA
Jesiotr, M:
Mil Inst Med, Dept Pathol, Warsaw, Poland
Bodnar, L:
Mil Inst Med, Dept Oncol, Warsaw, Poland
Quintela-Fandino, M:
Spanish Natl Canc Res Ctr CNIO, Breast Canc Clin Res Unit, Madrid, Spain
Lopez-Bigas, N:
Pompeu Fabra Univ UPF, Dept Expt & Hlth Sci, Barcelona Biomed Res Pk, Barcelona, Spain
ICREA, Barcelona, Spain
Valdes-Mas, R:
Univ Oviedo, Univ Inst Oncol Asturias, Dept Biochem & Mol Biol, Oviedo, Spain
Puente, XS:
Univ Oviedo, Univ Inst Oncol Asturias, Dept Biochem & Mol Biol, Oviedo, Spain
Vinals, F:
ICO, Angiogenesis Res Grp, ProCURE, IDIBELL, Barcelona, Spain
Hernandez-Losa, J:
Vall Hebron Univ Hosp, Dept Pathol, Barcelona, Spain
Cajal, SRY:
Vall Hebron Univ Hosp, Dept Pathol, Barcelona, Spain
Garcia-Alonso, L:
European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England
Saez-Rodriguez, J:
European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England
Esteller, M:
ICREA, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Spain
Sierra, A:
Cent Univ Catalonia, Univ Vic, Fac Sci & Tech,Mol & Translat Oncol Lab, Biomed Res Inst August Pi & Sunyer IDIBAPS,Biomed, Barcelona, Spain
Cent Univ Catalonia, Univ Vic, Fac Sci & Tech, Syst Biol Dept, Barcelona, Spain
Martin-Martin, N:
Ctr Cooperat Res Biosci CIC bioGUNE, Derio, Spain
Matheu, A:
Biodonostia Res Inst, Oncol Dept, Oncol Sect, San Sebastian, Spain
Basque Fdn Sci, IKERBASQUE, Bilbao, Spain
Carracedo, A:
Ctr Cooperat Res Biosci CIC bioGUNE, Derio, Spain
Basque Fdn Sci, IKERBASQUE, Bilbao, Spain
Univ Basque Country UPV EHU, Dept Biochem & Mol Biol, Bilbao, Spain
Nanjundan, M:
Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA
Cortes, J:
Vall Hebron Univ Hosp, VHIO, Dept Med Oncol, Barcelona, Spain
Lazaro, C:
IDIBELL, ICO, Hereditary Canc Programme, Barcelona, Spain
Odero, MD:
Univ Navarra, Ctr Appl Med Res CIMA, Pamplona, Spain
Univ Navarra, Dept Biochem & Genet, Pamplona, Spain
Martens, JWM:
Erasmus Univ, Med Ctr, Daniel den Hoed Canc Ctr, Canc Genom Ctr,Dept Med Oncol, Rotterdam, Netherlands
Moreno-Bueno, G:
Autonomous Univ Madrid UAM, Hosp La Paz Inst Hlth Res IdiPAZ, Dept Biochem, Biomed Res Inst Alberto Sols Spanish Natl Res Cou, Madrid, Spain
MD Anderson Int Fdn, Madrid, Spain
Barcellos-Hoff, MH:
NYU, Sch Med, Dept Radiat Oncol, New York, NY 10003 USA
Villanueva, A:
IDIBELL, ICO, Chemoresistance & Predict Factors Lab, ProCURE, Barcelona, Spain
Gomis, RR:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Oncol Program, Baldiri Reixac 10, Barcelona 08028, Spain
ICREA, Barcelona, Spain
Pujana, MA:
Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Breast Canc & Syst Biol Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain
Green Published, hybrid, Green Submitted
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