LAUSR

The diagnosis of brain metastasis involves high morbidity and mortality and remains as an unmet clinical need in spite of being the most common tumor in the brain. Brain metastasis affects between 10-30% of cancer patients with 200.000 new cases yearly only in the US. Increasing evidences point out the relevance of the microenvironment to understand the biology of brain colonization by metastatic cells, however translation strategies targeting it are lacking. We have identified altered signaling pathways in pro-metastatic reactive astrocytes (RA), and translated that into a novel therapeutic application for brain metastasis. Specifically we have identified a subpopulation of RA characterized by activated STAT3 pathway (pSTAT3+). This subpopulation is located in the vicinity of metastatic lesions intermingled with pSTAT3- RA in several experimental models and in 89% of human brain metastases independently of the primary tumor source. The pro-metastatic behaviour of RA is regulated by the activation of the STAT3 pathway, which modulates the immune system locally promoting the survival of cancer cells. Specifically the secretome of pSTAT3+ RA decreases the anti-tumor activity of CD8+ T cells as well as promotes the expansion of the pro-tumor population of CD74+ microglia/macrophage, which infiltrates metastasis cores. Interestingly, the immunosuppressive nature of pSTAT3+ RA is linked to the acquisition of stem cell-like properties, which might reflect the misuse of brain responses to injury instigated by the presence of cancer cells. Genetic and pharmacologic approaches targeting STAT3 in RA impair the progression of brain metastasis, even at advanced stages of the disease. Moreover, a safe and orally bioavailable STAT3 inhibitor reduced brain metastasis in 75% of 18 stage IV lung adenocarcinoma patients with established brain metastases, improving the outcome of the disease by increasing patient survival from 4 to 15 months. Besides increasing therapeutic opportunities for patients with brain metastasis, we have described for the first time the role of reactive astrocytes as regulators of local immunosuppression in brain metastasis as well as the importance of uncovering the heterogeneity within the metastasis-associated microenvironment. Citation Format: Neibla Priego, Lucia Zhu, Catia Monteiro, Manon Mulders, David Wasilewski, Wendy Bindeman, Laura Doglio, Elena Martinez-Saez, Santiago Ramon y Cajal, Coral Fustero-Torre, Elena Pineiro-Yanez, Aurelio Hernandez-Lain, Valeria Poli, Javier A. Menendez, Ricardo Soffietti, Joaquim Bosch-Barrera, Manuel Valiente. Stat3 labels a subpopulation of reactive astrocytes required for brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2746.