Brain metastasis occurs in a large proportion of metastatic melanoma patients and is associated with a dismal prognosis. However, the molecular mechanisms that govern melanoma tropism to the brain remain poorly understood. MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, and have been recently shown to exert key roles during cancer metastasis. In this study we find that specific miRNAs may be important mediators of melanoma dissemination to the brain. First, we conducted a miRNA microarray analysis of metastatic melanoma tissues that revealed a subset of miRNAs differentially expressed in brain metastases (n=11) relative to other sites (n=48). A brain-specific signature comprised of seven miRNAs was further validated in an independent cohort of metastatic melanoma samples (n=36; 9 brain metastatic specimens). Then, we analyzed the trend of expression of those miRNAs during tumor progression by comparing their levels in primary tumors and their paired metastasis from patients with or without recurrence in the brain (n=18). Differential expression of some miRNAs was already evident at diagnosis in primary tumors that recurred in the brain, while for others it was acquired in the transition from primary to metastasis, suggesting that it may be a later event in tumor progression. Furthermore, in vitro modulation of specific signature miRNAs significantly altered the ability of melanoma cells to execute processes such as adhesion and transmigration through human brain endothelial cells and proliferation in human astrocytes conditioned media. Additionally, using an in vivo model of melanoma brain metastasis, we confirmed the capacity of specific miRNA alterations to promote melanoma cells’ competence to reach the brain. Finally, the analysis of potential downstream mediators of select miRNAs revealed the involvement of immuno-suppressive molecules, as well as inflammatory and chemotactic mediators in this process. Collectively, our results expand our understanding of the mechanisms that control melanoma brain metastasis, potentially revealing novel therapeutic avenues for patients for whom no viable approaches are currently available.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1946.