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 enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. 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 nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.

中文翻译：

---

积极选择的增强因子赋予骨肉瘤细胞转移能力。

转移是由肿瘤细胞获得的一系列复杂特征导致的，这与肿瘤发生所必需的特征不同。在这里，我们研究增强子元素对骨肉瘤转移表型的贡献。通过表观基因组分析，我们发现原发性和转移性人类肿瘤之间以及高肺转移性和非转移性骨肉瘤细胞系的近等基因对之间的增强子活性存在实质性差异。我们将这些区域称为转移性变异增强子基因座（Met-VELs）。Met-VEL在肺转移性定植过程中驱动基因表达的协调波。Met-VELs在基因组中非随机聚集，表明这些增强子的活性及其相关基因靶标的表达已被积极选择。作为这种因果关系的证据，骨肉瘤肺转移受到药理性BET抑制，Met-VEL激活的单个基因的敲除或功能性抑制，通过抑制Met-VELs激活的AP-1转录因子，Met-VEL相关基因表达的整体中断而受到抑制，例如编码凝血因子III /组织因子（F3）的编码。我们进一步表明，在F3位点的单个Met-VEL的基因缺失可阻断肺中转移性细胞的生长。这些发现表明，Met-VEL及其调节的基因在转移中发挥功能作用，并且可能是抗转移疗法的合适靶标。以及通过敲除或功能抑制由Met-VEL激活的单个基因，例如编码凝血因子III /组织因子（F3）的基因。我们进一步表明，在F3位点的单个Met-VEL的基因缺失可阻断肺中转移性细胞的生长。这些发现表明，Met-VEL及其调节的基因在转移中发挥功能作用，并且可能是抗转移疗法的合适靶标。以及通过敲除或功能抑制由Met-VEL激活的单个基因，例如编码凝血因子III /组织因子（F3）的基因。我们进一步表明，在F3位点的单个Met-VEL的基因缺失可阻断肺中转移性细胞的生长。这些发现表明，Met-VEL及其调节的基因在转移中发挥功能作用，并且可能是抗转移疗法的合适靶标。