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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All published non-commercial reagents can be made available upon request to the corresponding author. The proteomics data are available at PRIDE (PXD008956).
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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.
The authors declare no competing interests.
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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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