Positively selected enhancer elements endow tumor cells with metastatic competence

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in signature enhancer-histone marks between near-isogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets is positively selected. Osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL associated gene expression. Examination of H3K4me1, H3K27ac, and Dnase I Hypersensitivity data in highly and non-metastatic osteosarcoma cell line pairs (n=5 pairs) as well as primary and metastatic tumors in human patients (n=5 pairs). Global gene expression during metastatic progression in ex vivo model of lung metastasis was also examined for 3 cell line pairs.