Positively selected enhancer elements endow osteosarcoma cells with metastatic competence

James J. Morrow, Ian Bayles, Alister P.W. Funnell, Tyler E. Miller, Alina Saiakhova, Michael M. Lizardo, Cynthia F. Bartels, Maaike Y. Kapteijn, Stevephen Hung, Arnulfo Mendoza, Gursimran Dhillon, Daniel R. Chee, Jay T. Myers, Frederick Allen, Marco Gambarotti, Alberto Righi, Analisa Difeo, Brian P. Rubin, Alex Y. Huang, Paul S. MeltzerLee J. Helman, Piero Picci, Henri H. Versteeg, John A. Stamatoyannopoulos, Chand Khanna, Peter C. Scacheri

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)176-185
Number of pages10
JournalNature Medicine
Volume24
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Morrow, J. J., Bayles, I., Funnell, A. P. W., Miller, T. E., Saiakhova, A., Lizardo, M. M., Bartels, C. F., Kapteijn, M. Y., Hung, S., Mendoza, A., Dhillon, G., Chee, D. R., Myers, J. T., Allen, F., Gambarotti, M., Righi, A., Difeo, A., Rubin, B. P., Huang, A. Y., ... Scacheri, P. C. (2018). Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nature Medicine, 24(2), 176-185. https://doi.org/10.1038/nm.4475