Artículo del mes
julio 2018

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Neibla Priego, Lucía Zhu, Cátia Monteiro, Manon Mulders, David Wasilewski, Wendy Bindeman, Laura Doglio, Liliana Martínez, Elena Martínez-Saez, Santiago Ramón y Cajal, Diego Megías, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Lola Martínez, Eduardo Zarzuela, Javier Muñoz, Coral Fustero-Torre, Elena Piñeiro-Yáñez, Aurelio Hernández-Laín, Luca Bertero, Valeria Poli, Melchor Sanchez-Martinez, Javier A. Menendez, Riccardo Soffietti, Joaquim Bosch-Barrera & Manuel Valiente
En este trabajo hemos descrito que las células tumorales con distintos orígenes primarios que metastatizan al cerebro, son capaces de activar el factor de transcripción STAT3 en una subpoblación de astrocitos reactivos, bloqueando así la acción de distintos componentes del sistema inmune innato y adaptativo. Bloqueando la activación de STAT3 en los astrocitos reactivos, se produce una disminución de la metástasis cerebral en modelos animales y en pacientes humanos.
Resumen
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.
Referencia artículo:
Nature medicine. 2018;24(7):1024-35.
Sobre el grupo investigador
En el grupo de Metástasis cerebral del CNIO, establecido en el año 2015, buscamos entender la biología de la metástasis cerebral usando distintos modelos experimentales para encontrar nuevas dianas terapéuticas, con el fin de mejorar el tratamiento actual y esperanza de vida de los pacientes que sufren esta enfermedad. Para ello trabajamos con ratones modificados genéticamente o xenoinjertos derivados de pacientes (PDX) entre otras aproximaciones experimentales y aplicamos distintas terapias sistémicas o locales a nuestros modelos.