STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

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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Fig. 1: pSTAT3 labels a subpopulation of RAs associated with established brain metastasis independently of the origin of the primary tumor.
Fig. 2: Genetic targeting of Stat3 in RAs impairs the viability of brain metastasis.
Fig. 3: De novo-induced STAT3 activity confers a differential functional identity to RAs.
Fig. 4: pSTAT3+ RAs influence additional components of the brain microenvironment that belong to the innate and acquired immune system.
Fig. 5: Pharmacological targeting of pSTAT3+ RAs impairs the viability of brain metastasis in mice and humans.

Data availability

All published non-commercial reagents can be made available upon request to the corresponding author. The proteomics data are available at PRIDE (PXD008956).

Change history

  • 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.

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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.

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Correspondence to Manuel Valiente.

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Priego, N., Zhu, L., Monteiro, C. et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat Med 24, 1024–1035 (2018). https://doi.org/10.1038/s41591-018-0044-4

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