Mustafa, Dana A MPedrosa, Rute M S MSmid, Marcelvan der Weiden, Marcelde Weerd, VanjaNigg, Alex LBerrevoets, CorZeneyedpour, LonaPriego, NeiblaValiente, ManuelLuider, Theo MDebets, RenoMartens, John W MFoekens, John ASieuwerts, Anieta MKros, Johan M2024-12-102024-12-102018-04Acta Neuropathol . 2018 Apr;135(4):581-599.https://hdl.handle.net/20.500.12105/25873The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood-brain barrier (BBB) model. By co-culturing T lymphocytes with breast cancer cells, we confirmed that T cells increase the ability of breast cancer cells to cross the BBB. Proteomics analysis of the tumor cells revealed Guanylate-Binding Protein 1 (GBP1) as a key T lymphocyte-induced protein that enables breast cancer cells to cross the BBB. The GBP1 gene appeared to be up-regulated in breast cancer of patients who developed brain metastasis. Silencing of GBP1 reduced the ability of breast cancer cells to cross the in vitro BBB model. In addition, the findings were confirmed in vivo in an immunocompetent syngeneic mouse model. Co-culturing of ErbB2 tumor cells with activated T cells induced a significant increase in Gbp1 expression by the cancer cells. Intracardial inoculation of the co-cultured tumor cells resulted in preferential seeding to brain. Moreover, intracerebral outgrowth of the tumor cells was demonstrated. The findings point to a role of T cells in the formation of brain metastases in ER- breast cancers, and provide potential targets for intervention to prevent the development of cerebral metastases.J.M.K. received funding for this work by the Dutch Cancer Society (KWF) (EMCR 2009-4553). M.V. was supported by Beug Foundation's Prize for Metastasis Research 2017 (M.V.).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Blood–brain barrierBrain metastasisGBP1T cell responseAttribution-NonCommercial-NoDerivatives 4.0 International293502741354581-599Acta Neuropathologicaopen access