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It is well known that cancer patients with brain metastasis (BM) have a poor prognosis and current treatments are not effective. It has been shown that BM development is caused by molecular interactions between the tumor cells and the normal brain, constituting the so-called brain metastatic niche. In this respect, miRNAs delivered by exosomes released by the primary tumor cells seem to be an important factor in BM niche establishment yet the mechanisms behind this process is poorly understood. AIM The aim of this project was to determine miRNAs released by exosomes from melanomas that may be important in establishing the BM niche, and to validate these findings in vitro and in vivo. METHODS We performed a miRNA profiling on exosomes collected from 3 human melanoma BM cell lines and from human astrocytes and melanocytes, to determine the most important differently expressed miRNAs. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR-knockdown in BM cell lines, in an experimental animal/tumor model. RESULTS AND DISCUSSION The miRNA profiling showed that miR-146a was by far the most differentially upregulated miRNA in exosomes from melanoma BM cell lines, compared to exosomes from normal cells. Mir-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. These effects were reversed by adding anti-miR-146a to the experiments. In animal studies, knockdown of miR-146 in melanoma BM cells injected intracardially into nod/scid mice resulted in a significant reduction in BM burden, compared to wild type cells, and increased animal survival. CONCLUSIONS Inhibition of miR-146a reduces activation of the BM niche, leading to inhibition of BM development.

TMOD-04. INHIBITION OF MELANOMA BRAIN METASTASIS BY TARGETING miR146a