表观遗传学治疗通过破坏转移前微环境抑制转移，这一成果由美国约翰霍普金斯大学Malcolm V. Brock、Lin Shen、Stephen B. Baylin、Franck Housseau等研究人员合作完成。这一研究成果于2020年2月26日在线发表在《自然》杂志上。

Title: Epigenetic therapy inhibits metastases by disrupting premetastatic niches

Author: 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 Cui, Yujiao Wang, Yanni Wang, Weiqiang Zhang, Hariharan Easwaran, Alicia Hulbert, KiBem 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

Issue&Volume: 2020-02-26

Abstract: Cancer recurrence after surgery remains an unresolved clinical problem1,2,3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4,5,6. 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.

DOI: 10.1038/s41586-020-2054-x

Source: https://www.nature.com/articles/s41586-020-2054-x