Positively selected enhancer elements endow osteosarcoma cells with metastatic competence
Open accessAbstract
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.
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Triggering the haemostatic cascade is important for the early survival of disseminated osteosarcoma cells.
“Evidence further suggests that triggering the haemostatic cascade is important for the early survival of disseminated cells 75,76 .”
From Osteosarcoma (2022) · cites this paper as [75]
Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.
“These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”
From Osteosarcoma (2022) · cites this paper as [75]
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- Authors
- 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., Meltzer, P. S., Helman, L. J., Picci, P., Versteeg, H. H., Stamatoyannopoulos, J. A., Khanna, C., & Scacheri, P. C.
- Affiliations
- Case Western Reserve University (US)
- Altius Institute for Biomedical Sciences (US)
- National Institutes of Health (US)
- Leiden University Medical Center (NL)
- University of Washington (US)
- Istituto Ortopedico Rizzoli (IT)
- Case Comprehensive Cancer Center (US)
- Cleveland Clinic (US)
- Corresponding author
- Scacheri, Peter C
- ORCID
- Morrow, James J
- Funnell, Alister P W
- Miller, Tyler E
- Lizardo, Michael M
- Bartels, Cynthia F
- Kapteijn, Maaike Y
- Hung, Stevephen
- Mendoza, Arnulfo
- Myers, Jay T
- Gambarotti, Marco
- Righi, Alberto
- DiFeo, Analisa
- Rubin, Brian P
- Huang, Alex Y
- Meltzer, Paul S
- Helman, Lee J
- Picci, Piero
- Versteeg, Henri H
- Stamatoyannopoulos, John A
- Scacheri, Peter C
- Venue
- Nature Medicine
- Published
- 2018-01-15
- Volume
- 24
- Issue
- 2
- Pages
- 176-185
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5803371
- OpenAlex
- W2783862258
- Cited by
- 161
- References
- 70
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 28 · 2022: 18 · 2021: 23 · 2020: 24 · 2019: 19 · 2018: 10
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-04-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Case Western Reserve University
- Case Comprehensive Cancer Center, Case Western Reserve University (P30 CA043703, R01CA204279)
- National Institutes of Health (TL1TR002549)
- National Cancer Institute (R01CA193677, F31CA213965, R21CA218790, R01CA204279, R01CA160356, F30CA186633, P30CA043703)
- National Institute of General Medical Sciences (T32GM007250)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- osteosarcoma, lung metastasis, enhancers, positive selection, AP-1 transcription factor, tissue factor, BET inhibition, epigenetic profiling, metastatic colonization, anti-metastatic therapy
- MeSH terms
- Bromodomain Containing Proteins, Enhancer Elements, Genetic, Humans, Lung Neoplasms, Neoplasm Metastasis, Proteins, Osteosarcoma, Selection, Genetic, Thromboplastin, Genome, Human, Gene Expression Regulation, Neoplastic, Transcription Factor AP-1, Cell Line, Tumor, Epigenomics, Tumor Microenvironment, Carcinogenesis
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