Subjects

Abstract

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

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Change history

  • Correction 19 June 2018

    In the version of this article originally published, the names of three authors were incorrect. The authors were listed as “Coral Fustero-Torres”, “Elena Pineiro” and “Melchor Sánchez-Martínez”. Their respective names are “Coral Fustero-Torre”, “Elena Piñeiro-Yáñez” and “Melchor Sanchez-Martinez”. The errors have been corrected in the print, HTML and PDF versions of this article.

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Acknowledgements

We want to thank the CNIO Core Facilities for their excellent assistance. We also thank F.X. Real, O. Marín, M. Serrano, O. Fernandez-Capetillo and M. Soengas for critically reading the manuscript, P. Bos for advice with CD8+ T cell experiments, J. Massagué (MSKCC) for the BrM cell lines, MEDA for Legasil, M. A. Pérez (University of Copenhagen), H. Peinado (CNIO), M. Soengas (CNIO) and M. Squatrito (CNIO) for reagents. This work was supported by MINECO grants MINECO-Retos SAF2014-57243-R (M.V.), MINECO-Europa Excelencia SAF2015-62547-ERC (M.V.), FERO Grant for Research in Oncology (M.V.), Melanoma Research Alliance Young Investigator Award (M.V.), AECC Coordinated Translational Groups (M.V., E.M.-S. and S.R.y.C), SEOM (J.B.-B.), Pfizer WI190764 (J.B.-B.), Meda Pharma (J.B.-B.), Armangué Family Fund (J.A.M. and J.B.-B.), La Caixa-Severo Ochoa International PhD Program Fellowship (L.Z.), FCT PhD Fellowship SFRH/BD/100089/2014 (C.M.), the Fulbright Program (W.B.). M.V. is a Ramón y Cajal Investigator (RYC-2013-13365). This work is dedicated to the memory of María Jesús Cortés Garín.

Author information

Author notes

    • David Wasilewski

    Present address: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Laura Doglio

    Present address: Centre for Developmental Neurobiology, King’s College London, London, UK

Affiliations

  1. Brain Metastasis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    • Neibla Priego
    • , Lucía Zhu
    • , Cátia Monteiro
    • , Manon Mulders
    • , David Wasilewski
    • , Wendy Bindeman
    • , Laura Doglio
    • , Liliana Martínez
    •  & Manuel Valiente
  2. Pathology Department, Vall d’Hebron Hospital, Barcelona, Spain

    • Elena Martínez-Saez
    •  & Santiago Ramón y Cajal
  3. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain

    • Elena Martínez-Saez
    •  & Santiago Ramón y Cajal
  4. Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    • Diego Megías
  5. Experimental Therapeutics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain

    • Elena Hernández-Encinas
    •  & Carmen Blanco-Aparicio
  6. Flow Cytometry Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    • Lola Martínez
  7. ProteoRed-ISCIII. Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    • Eduardo Zarzuela
    •  & Javier Muñoz
  8. Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    • Coral Fustero-Torre
    •  & Elena Piñeiro-Yáñez
  9. Neuropathology Unit, Hospital Universitario 12 de Octubre Research Institute, Madrid, Spain

    • Aurelio Hernández-Laín
  10. Medical Sciences Department, Division of Pathology, University and City of Health and Science University Hospital of Turin, Turin, Italy

    • Luca Bertero
  11. Molecular Biotechnology Centre, University of Turin, Turin, Italy

    • Valeria Poli
  12. Mind the Byte, Barcelona, Spain

    • Melchor Sanchez-Martinez
  13. Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain

    • Javier A. Menendez
  14. Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain

    • Javier A. Menendez
    •  & Joaquim Bosch-Barrera
  15. Neuro-Oncology Department, University and City of Health and Science University Hospital of Turin, Turin, Italy

    • Riccardo Soffietti
  16. Department of Medical Sciences, Medical School, University of Girona, Girona, Spain

    • Joaquim Bosch-Barrera
  17. Catalan Institute of Oncology (ICO), Dr. Josep Trueta University Hospital, Girona, Spain

    • Joaquim Bosch-Barrera

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Contributions

N.P. and M.V. designed and performed the experiments, analyzed the data and wrote the manuscript. L.Z., C.M., M.M., D.W., W.B., L.D. and Liliana M. performed the experiments and analyzed the data. E.H.-E., C.B.-A. and L.Z. performed the pharmacokinetic experiments and analyzed the data. E.Z., J.M. and N.P. performed the proteomic experiments and analyzed the data. C.F.-T. and E.P. performed the bioinformatics analysis. V.P. provided the Stat3loxP/loxP mice. M.S.-M. and J.A.M. performed the in silico modeling. J.B.-B. performed the clinical study with Legasil. E.M.-S., S.R.y.C., A.H.-L., L.B. and R.S. provided the human samples and determined suitability for study. E.M.-S. scored the human samples. D.M. provided technical support with microscopy. Lola M. provided technical support with flow cytometry.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Manuel Valiente.

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