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Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

ABSTRACT: 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.

SUBMITTER: Lu Z

PROVIDER: S-EPMC8765085 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

Lu Zhihao Z Zou Jianling J Li Shuang S Topper Michael J MJ Tao Yong Y Zhang Hao H Jiao Xi X Xie Wenbing W Kong Xiangqian X Vaz Michelle M Li Huili H Cai Yi Y Xia Limin L Huang Peng P Rodgers Kristen K Lee Beverly B Riemer Joanne B JB Day Chi-Ping CP Yen Ray-Whay Chiu RC Cui Ying Y Wang Yujiao Y Wang Yanni Y Zhang Weiqiang W Easwaran Hariharan H Hulbert Alicia A Kim KiBem K Juergens Rosalyn A RA Yang Stephen C SC Battafarano Richard J RJ Bush Errol L EL Broderick Stephen R SR Cattaneo Stephen M SM Brahmer Julie R JR Rudin Charles M CM Wrangle John J Mei Yuping Y Kim Young J YJ Zhang Bin B Wang Ken Kang-Hsin KK Forde Patrick M PM Margolick Joseph B JB Nelkin Barry D BD Zahnow Cynthia A CA Pardoll Drew M DM Housseau Franck F Baylin Stephen B SB Shen Lin L Brock Malcolm V MV

Nature 20200226 7798

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, l ...[more]

PMID: 32103175

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Project description:IntroductionObesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer.MethodsWe used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays.ResultsETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice.DiscussionIn this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the "seed and soil hypothesis." Our results also support the ETBF-induced "parallel model" of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.

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Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

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Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

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