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STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Authors :
Javier A. Menendez
Eduardo Zarzuela
Elena Hernández-Encinas
Neibla Priego
Manon Mulders
Riccardo Soffietti
Diego Megías
Valeria Poli
Joaquim Bosch-Barrera
Liliana Martínez
Santiago Ramón y Cajal
Laura Doglio
Javier Muñoz
Manuel Valiente
Lucía Zhu
Lola Martínez
Luca Bertero
Wendy Bindeman
Coral Fustero-Torre
David Wasilewski
Cátia Monteiro
Melchor Sanchez-Martinez
Elena Piñeiro-Yáñez
Aurelio Hernández-Laín
Carmen Blanco-Aparicio
Elena Martínez-Sáez
Source :
Nature medicine. 24(7)
Publication Year :
2017

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. Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors.

Details

ISSN :
1546170X
Volume :
24
Issue :
7
Database :
OpenAIRE
Journal :
Nature medicine
Accession number :
edsair.doi.dedup.....c6e56eff85fe535456625716c5c389f7