The brain offers a unique microenvironment to which malignant melanoma frequently spreads leading to dismal prognosis for the patients. The molecular determinants that promote melanoma brain metastases however, remain largely unknown. Here, we show an experimental strategy utilizing two species of immune-compromised animals in a metastasis model to generate in vivo-cultivated metastatic tissues along with their corresponding host tissues in order to identify molecular events associated with brain metastases. The study was based on the melanoma cell lines, Melmet 1 and Melmet 5 with opposing phenotypes (invasive/proliferative, respectively) in the in vitro setting and distinct metastatic patterns in vivo, where Melmet 1 showed a preference to the brain. Transcriptional changes in the melanoma cells, as induced by the brain-microenvironment in both host species, revealed the opportunistic nature of melanoma in this context. We detected transitioning from the invasive phenotype to the proliferative phenotype, as the brain metastases passed from early to late growth phase. Of significance, we identified a brain-adaptive phenotype with synaptic characteristics and where glutamate signaling and Ca2+-dependent effectors played a central role. The brain-adaptive phenotype was more prominent in the earlier metastatic growth phases compared to a later phase. Analysis of host tissue uncovered a cooperative inflammatory microenvironment formed by activated host cells. Altogether, this suggests that acquisition of the brain-adaptive phenotype in a permissive environment might be critical for the establishment of metastatic growth in the brain microenvironment and further, targeting glutamate signaling may represent a therapeutic approach in brain metastasis. Global network modeling and functional annotation analysis revealed that several of the central molecular factors and pathways mediating melanoma brain metastasis in this study, are also central to other pathological diseases, in particular neurodegenerative diseases. The identification of essential molecular networks that operate to promote the brain-adaptive phenotype is of clinical relevance, as they represent leads to urgently needed therapeutic targets.

Citation Format: Vigdis Nygaard, Lina Prasmickaite, Kotryna Vasiliauskaite, Trevor Clancy, Eivind Hovig. Characterization of malignant melanoma growth triggered by the brain microenvironment in experimental metastasis models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4876. doi:10.1158/1538-7445.AM2014-4876