Journal Article

Positively selected enhancer elements endow osteosarcoma cells with metastatic competence

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

2018

Overview

Peter Scacheri and colleagues report that the activity of enhancer elements in metastatic osteosarcoma is distinct from that in primary tumors and plays a functional role in metastatic progression of osteosarcoma. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1344 / 631/67/1798 / 631/67/322 / 631/67/69 / 64 / Activator protein 1 / Biocompatibility / Biomedicine / Bone cancer / Bromodomain Containing Proteins / Cancer metastasis / Cancer Research / Carcinogenesis - genetics / Cell Line, Tumor / Cells / Clonal deletion / Coagulation / Colonization / Development and progression / Enhancer Elements, Genetic - genetics / Enhancers / Epigenomics / Gene deletion / Gene expression / Gene Expression Regulation, Neoplastic / Genes / Genetic aspects / Genome, Human - genetics / Genomes / Humans / Infectious Diseases / Kinases / Loci / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Lung Neoplasms - secondary / Lungs / Metabolic Diseases / Metastases / Metastasis / Molecular Medicine / Neoplasm Metastasis - genetics / Neurosciences / Osteosarcoma / Osteosarcoma - genetics / Osteosarcoma - pathology / Osteosarcoma cells / Pharmacology / Phenotypes / Proteins - antagonists & inhibitors / Proteins - genetics / Sarcoma / Selection, Genetic / Thromboplastin - genetics / Tissue factor / Trace elements / Transcription Factor AP-1 - antagonists & inhibitors / Transcription Factor AP-1 - genetics / Transcription factors / Tumor cells / Tumor Microenvironment - genetics / Tumorigenesis / Tumors