Epigenetic therapy inhibits metastases by disrupting premetastatic niches
Open accessAbstract
Cancer recurrence after surgery remains an unresolved clinical problem 1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites 4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment 6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.
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ENT plus DNA demethylation agent AZA promotes migration of myeloid cells to the metastatic niche to suppress metastasis in different tumor models.
“in a recent report, ENT plus DNA demethylation agent AZA was found to promote the migration of myeloid cells to the metastatic niche to suppress metastasis in different tumor models56.”
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- Authors
- Lu, Z., Zou, J., Li, S., Topper, M. J., Tao, Y., Zhang, H., Jiao, X., Xie, W., Kong, X., Vaz, M., Li, H., Cai, Y., Xia, L., Huang, P., Rodgers, K., Lee, B., Riemer, J. B., Day, C.-P., Yen, R.-W. C., Cui, Y., Wang, Y., Wang, Y., Zhang, W., Easwaran, H., Hulbert, A., Kim, K., Juergens, R. A., Yang, S. C., Battafarano, R. J., Bush, E. L., Broderick, S. R., Cattaneo, S. M., Brahmer, J. R., Rudin, C. M., Wrangle, J., Mei, Y., Kim, Y. J., Zhang, B., Wang, K. K.-H., Forde, P. M., Margolick, J. B., Nelkin, B. D., Zahnow, C. A., Pardoll, D. M., Housseau, F., Baylin, S. B., Shen, L., & Brock, M. V.
- Affiliations
- Peking University Cancer Hospital (CN)
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Juravinski Cancer Centre (CA)
- Anne Arundel Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Medical University of South Carolina (US)
- Vanderbilt University (US)
- Corresponding author
- Housseau, Franck
- Baylin, Stephen B.
- Shen, Lin
- Brock, Malcolm V.
- ORCID
- Zou, Jianling
- Li, Shuang
- Topper, Michael J.
- Tao, Yong
- Zhang, Hao
- Jiao, Xi
- Xie, Wenbing
- Kong, Xiangqian
- Vaz, Michelle
- Li, Huili
- Cai, Yi
- Xia, Limin
- Huang, Peng
- Rodgers, Kristen
- Lee, Beverly
- Riemer, Joanne B.
- Day, Chi-Ping
- Cui, Ying
- Wang, Yujiao
- Wang, Yanni
- Zhang, Weiqiang
- Easwaran, Hariharan
- Hulbert, Alicia
- Juergens, Rosalyn A.
- Yang, Stephen C.
- Bush, Errol L.
- Broderick, Stephen R.
- Brahmer, Julie R.
- Rudin, Charles M.
- Wrangle, John
- Mei, Yuping
- Kim, Young J.
- Zhang, Bin
- Wang, Ken Kang-Hsin
- Forde, Patrick M.
- Margolick, Joseph B.
- Nelkin, Barry D.
- Zahnow, Cynthia A.
- Pardoll, Drew M.
- Housseau, Franck
- Baylin, Stephen B.
- Shen, Lin
- Venue
- Nature
- Published
- 2020-02-26
- Volume
- 579
- Issue
- 7798
- Pages
- 284-290
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8765085
- OpenAlex
- W3006996572
- Cited by
- 330
- References
- 36
- Citations by year
- 2026: 16 · 2025: 46 · 2024: 57 · 2023: 59 · 2022: 51 · 2021: 65 · 2020: 35
- FWCI
- 19.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R21CA126265, P30CA008748, P30CA006973)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- epigenetic therapy, pre-metastatic niche, myeloid-derived suppressor cells, lung metastasis, adjuvant therapy, hypomethylating agents, histone deacetylase inhibitors, azacitidine, entinostat, CCR2, CXCR2, macrophage differentiation, tumor recurrence, tumour cell dissemination, breast cancer, esophageal cancer
- MeSH terms
- Myeloid-Derived Suppressor Cells, Animals, Azacitidine, Benzamides, Cell Differentiation, Cell Movement, Disease Models, Animal, Neoplasm Metastasis, Neoplasms, Pyridines, Genetic Therapy, Down-Regulation, Chemotherapy, Adjuvant, Receptors, Interleukin-8B, Epigenesis, Genetic, Mice, Receptors, CCR2, Tumor Microenvironment
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