Journal Article

Epigenetic therapy inhibits metastases by disrupting premetastatic niches

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

2020

Overview

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. In mouse models of pulmonary metastasis, adjuvant epigenetic therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 14/35 / 14/63 / 38/61 / 38/77 / 45/90 / 59 / 631/67/1059 / 64/110 / 64/60 / 692/308/575 / 82/1 / 82/80 / 96/2 / Analysis / Animal models / Animals / Apoptosis / Azacitidine - pharmacology / Azacytidine / Benzamides - pharmacology / Bone marrow / Bone surgery / Breast / Cancer / Cancer therapies / CCR2 protein / Cell culture / Cell Differentiation / Cell Movement - drug effects / Chemotherapy / Chemotherapy, Adjuvant / Control / CXCR2 protein / Disease Models, Animal / Disruption / DNA methyltransferase / Down-Regulation - drug effects / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Esophageal cancer / Esophagus / Gene expression / Gene therapy / Genetic Therapy / Histone deacetylase / Humanities and Social Sciences / Lung cancer / Lungs / Macrophages / Metastases / Metastasis / Methods / Mice / Monocyte chemoattractant protein 1 / multidisciplinary / Myeloid cells / Myeloid-Derived Suppressor Cells - cytology / Myeloid-Derived Suppressor Cells - physiology / Neoplasm Metastasis - therapy / Neoplasms - surgery / Neoplasms - therapy / Phenotypes / Pyridines - pharmacology / Receptors, CCR2 - genetics / Receptors, Interleukin-8B - genetics / Science / Science (multidisciplinary) / Suppressor cells / Surgery / Survival / Tumor Microenvironment - drug effects / Tumors