Enhancer-Driven Gene Expression Changes Facilitate Metastasis

Osteosarcoma is a bone malignancy that frequently metastasizes to the lung. In order to colonize the metastatic site, tumor cells shift their transcriptional output to adapt to the local microenvironment, but it is not clear what genetic or epigenetic mechanisms drive this shift. To determine the contribution of enhancer elements to the metastatic phenotype, Morrow and colleagues performed epigenomic profiling of primary and metastatic osteosarcomas and metastatic and nonmetastatic osteosarcoma cell lines. Loci with differential enhancer activity in primary versus metastatic tumors and cells were termed metastatic variant enhancer loci (Met-VEL). On average, 9.3% of enhancers were gained in metastatic samples and 16.4% of enhancers were lost. Twenty-two percent of Met-VELs were distributed in dense clusters across the genome, often in close proximity to individual genes, suggesting a nonrandom acquisition due to selective pressure during metastasis, and Met-VELs were associated with increased gene expression. In an ex vivo mouse model of osteosarcoma lung metastasis, the difference in Met-VEL associated gene expression was even greater between parental and metastatic cells than in in vitro cultures, indicating a dynamic modulation of gene expression as tumor cells engage the lung microenvironment. Further, expression of Met-VEL–associated genes was required for metastatic colonization, including genes with gained Met-VEL clusters (F3, FBXO42, FLNA, and FOXO3) and genes that encode AP1 complex transcription factors that bind to Met-VELs (FOS and FOSL1). Thus, disrupting Met-VEL–associated gene expression with BET inhibitors or AP1 transcription factor depletion reduced metastasis. F3 was highly expressed in lung metastases from patients with osteosarcoma, and in an in vivo metastasis model, metastatic osteosarcoma cells expressed higher levels of F3 than nonmetastatic cells. F3 depletion inhibited metastasis in a spontaneous metastasis model but did not suppress primary tumor growth. These findings indicate that altered enhancer activity at Met-VELs can drive metastasis, suggesting potential targets for antimetastatic therapies.

Morrow JJ, Bayles I, Funnell APW, Miller TE, Saiakhova A, Lizardo MM, et al. Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nat Med 2018;24:176–85.

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