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

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

doi:10.1038/onc.2016.427

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

Oncogene. 2017 May 11;36(19):2737-2749. doi: 10.1038/onc.2016.427. Epub 2016 Dec 19.

Authors

F Mateo¹, E J Arenas², H Aguilar¹, J Serra-Musach¹, G Ruiz de Garibay¹, J Boni¹, M Maicas³, S Du⁴, F Iorio^{5

6}, C Herranz-Ors¹, A Islam⁷, X Prado¹, A Llorente¹, A Petit⁸, A Vidal⁸, I Català⁸, T Soler⁸, G Venturas⁸, A Rojo-Sebastian⁹, H Serra¹⁰, D Cuadras¹¹, I Blanco¹², J Lozano¹³, F Canals¹⁴, A M Sieuwerts¹⁵, V de Weerd¹⁵, M P Look¹⁵, S Puertas¹⁶, N García¹, A S Perkins¹⁷, N Bonifaci¹, M Skowron¹, L Gómez-Baldó¹, V Hernández¹⁸, A Martínez-Aranda¹⁸, M Martínez-Iniesta¹⁶, X Serrat¹⁹, J Cerón¹⁹, J Brunet²⁰, M P Barretina²¹, M Gil²², C Falo²², A Fernández²², I Morilla²², S Pernas²², M J Plà²³, X Andreu²⁴, M A Seguí²⁵, R Ballester²⁶, E Castellà²⁷, M Nellist²⁸, S Morales²⁹, J Valls²⁹, A Velasco²⁹, X Matias-Guiu²⁹, A Figueras¹⁰, J V Sánchez-Mut³⁰, M Sánchez-Céspedes³⁰, A Cordero³⁰, J Gómez-Miragaya³⁰, L Palomero¹, A Gómez³⁰, T F Gajewski³¹, E E W Cohen³², M Jesiotr³³, L Bodnar³⁴, M Quintela-Fandino³⁵, N López-Bigas^{36

37}, R Valdés-Mas³⁸, X S Puente³⁸, F Viñals¹⁰, O Casanovas¹⁰, M Graupera¹⁰, J Hernández-Losa³⁹, S Ramón Y Cajal³⁹, L García-Alonso⁵, J Saez-Rodriguez⁵, M Esteller^{30

37

40}, A Sierra⁴¹, N Martín-Martín⁴², A Matheu^{43

44}, A Carracedo^{42

44

45}, E González-Suárez³⁰, M Nanjundan⁴⁶, J Cortés⁴⁷, C Lázaro¹², M D Odero³, J W M Martens¹⁵, G Moreno-Bueno⁴⁸, M H Barcellos-Hoff⁴, A Villanueva¹⁶, R R Gomis^{2

37}, M A Pujana¹

Affiliations

¹ Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.
² Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
³ Centre for Applied Medical Research (CIMA) and Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
⁴ Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA.
⁵ European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, UK.
⁶ Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
⁷ Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.
⁸ Department of Pathology, University Hospital of Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
⁹ Department of Pathology, MD Anderson Cancer Center, Madrid, Spain.
¹⁰ Angiogenesis Research Group, ProCURE, ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
¹¹ Statistics Unit, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
¹² Hereditary Cancer Programme, ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
¹³ Department of Molecular Biology and Biochemistry, Málaga University, and Molecular Oncology Laboratory, Mediterranean Institute for the Advance of Biotechnology and Health Research (IBIMA), University Hospital Virgen de la Victoria, Málaga, Spain.
¹⁴ ProteoRed-Instituto de Salud Carlos III, Proteomic Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.
¹⁵ Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Cancer Genomics Centre, Rotterdam, The Netherlands.
¹⁶ Chemoresistance and Predictive Factors Laboratory, ProCURE, ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
¹⁷ University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY, USA.
¹⁸ Biological Clues of the Invasive and Metastatic Phenotype Laboratory, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
¹⁹ Cancer and Human Molecular Genetics, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
²⁰ Hereditary Cancer Programme, ICO, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
²¹ Department of Medical Oncology, ICO, IDIBGI, Girona, Spain.
²² Department of Medical Oncology, ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
²³ Department of Gynecology, University Hospital of Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
²⁴ Department of Pathology, Parc Taulí Hospital Consortium, Sabadell, Barcelona, Spain.
²⁵ Medical Oncology Service, Parc Taulí Hospital Consortium, Sabadell, Barcelona, Spain.
²⁶ Department of Radiation Oncology, University Hospital Germans Trias i Pujol, ICO, Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain.
²⁷ Department of Pathology, University Hospital Germans Trias i Pujol, ICO, IGTP, Badalona, Barcelona, Spain.
²⁸ Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
²⁹ Hospital Arnau de Vilanova, University of Lleida, Biomedical Research Institute of Lleida (IRB Lleida), Lleida, Spain.
³⁰ Cancer Epigenetics and Biology Program (PEBC), IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
³¹ Departments of Pathology and Medicine, University of Chicago, Chicago, IL, USA.
³² Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
³³ Department of Pathology, Military Institute of Medicine, Warsaw, Poland.
³⁴ Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
³⁵ Breast Cancer Clinical Research Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
³⁶ Department of Experimental and Health Sciences, Barcelona Biomedical Research Park, Pompeu Fabra University (UPF), Barcelona, Spain.
³⁷ Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
³⁸ Department of Biochemistry and Molecular Biology, University Institute of Oncology of Asturias, University of Oviedo, Oviedo, Spain.
³⁹ Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
⁴⁰ Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain.
⁴¹ Molecular and Translational Oncology Laboratory, Biomedical Research Center CELLEX-CRBC, Biomedical Research Institute 'August Pi i Sunyer' (IDIBAPS), and Systems Biology Department, Faculty of Science and Technology, University of Vic, Central University of Catalonia, Barcelona, Spain.
⁴² Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Spain.
⁴³ Neuro-Oncology Section, Oncology Department, Biodonostia Research Institute, San Sebastian, Spain.
⁴⁴ Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
⁴⁵ Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
⁴⁶ Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
⁴⁷ Department of Medical Oncology, VHIO, Vall d'Hebron University Hospital, Barcelona, Spain.
⁴⁸ Department of Biochemistry, Autonomous University of Madrid (UAM), Biomedical Research Institute 'Alberto Sols' (Spanish National Research Council (CSIC)-UAM), Translational Research Laboratory, Hospital La Paz Institute for Health Research (IdiPAZ), and MD Anderson International Foundation, Madrid, Spain.

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adult
Aged
Breast Neoplasms / genetics*
Breast Neoplasms / pathology
Carrier Proteins / genetics
Cell Proliferation / genetics
DNA-Binding Proteins / genetics*
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Lung Neoplasms / secondary
MCF-7 Cells
MDS1 and EVI1 Complex Locus Protein
Microfilament Proteins / genetics
Middle Aged
Neoplasm Metastasis
Osteonectin / genetics
Proto-Oncogenes / genetics*
Regulatory-Associated Protein of mTOR
SOX9 Transcription Factor / genetics*
Signal Transduction / genetics
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics*
Transcription Factors / genetics*
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
DNA-Binding Proteins
FSCN1 protein, human
MDS1 and EVI1 Complex Locus Protein
MECOM protein, human
Microfilament Proteins
Osteonectin
RPTOR protein, human
Regulatory-Associated Protein of mTOR
SOX9 Transcription Factor
SOX9 protein, human
SPARC protein, human
Transcription Factors
MTOR protein, human
TOR Serine-Threonine Kinases

Grants and funding

WT_/Wellcome Trust/United Kingdom