Epigenetic therapy inhibits metastases by disrupting premetastatic niches

Zhihao Lu, Jianling Zou, Shuang Li, Michael J. Topper, Yong Tao, Hao Zhang, Xi Jiao, Wenbing Xie, Xiangqian Kong, Michelle Vaz, Huili Li, Yi Cai, Limin Xia, Peng Huang, Kristen Rodgers, Beverly Lee, Joanne B. Riemer, Chi Ping Day, Ray Whay Chiu Yen, Ying CuiYujiao Wang, Yanni Wang, Weiqiang Zhang, Hariharan Easwaran, Alicia Hulbert, Ki Bem Kim, Rosalyn A. Juergens, Stephen C. Yang, Richard J. Battafarano, Errol L. Bush, Stephen R. Broderick, Stephen M. Cattaneo, Julie R. Brahmer, Charles M. Rudin, John Wrangle, Yuping Mei, Young J. Kim, Bin Zhang, Ken Kang Hsin Wang, Patrick M. Forde, Joseph B. Margolick, Barry D. Nelkin, Cynthia A. Zahnow, Drew M. Pardoll, Franck Housseau, Stephen B. Baylin, Lin Shen, Malcolm V. Brock

Research output: Contribution to journalArticle

Abstract

Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. 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.

Original languageEnglish (US)
Pages (from-to)284-290
Number of pages7
JournalNature
Volume579
Issue number7798
DOIs
StatePublished - Mar 12 2020

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Epigenetic therapy inhibits metastases by disrupting premetastatic niches'. Together they form a unique fingerprint.

  • Cite this

    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., ... Brock, M. V. (2020). Epigenetic therapy inhibits metastases by disrupting premetastatic niches. Nature, 579(7798), 284-290. https://doi.org/10.1038/s41586-020-2054-x