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Discovery of CCL18 antagonist blocking breast cancer metastasis

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Abstract

Our previous studies have proved that CCL18 is the most secreted chemokine in breast cancer microenvironment by tumor associated macrophages (TAMs). CCL18 promotes breast cancer invasiveness by binding to its cognate receptor PITPNM3 and activating the downstream signaling pathways. The high level of CCL18 in serum or tumor stroma is associated with tumor metastasis and poor patients overall survival. In this study, we identify an effective small molecular compound (SMC) to antagonize the effect of CCL18. We screen more than 1000 SMCs from Sun Yat-sen University SMC library and select 15 top scored SMCs by using computer-aided virtual screening based on the structure of CCL18. Then in vitro cell migration assay narrows down the selected 15 SMCs to the most effective SMC-21598. We find 10 µM SMC-21598 significantly inhibits CCL18-induced breast cancer cells adherence, invasiveness, and migration. Our further surface plasmon resonance (SPR), fluorescence spectroscopy and isothermal titration calorimetry (ITC) assays reveal that SMC-21598 binds tightly to CCL18, which blocks the binding of CCL18 with its receptor PITPNM3. The in vivo animal experiments show that SMC-21598 doesn’t significantly affect xenografts growth, but inhibits lung metastasis. Our study provides a potential lead compound to antagonize CCL18 function. It would be of great significance to develop SMC drugs to ameliorate breast cancer metastasis and prolong patients’ survival.

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Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (81672622, 81772828, 81720108029, 81621004, 81490750, 81272900, 81172537), the National Key Research and Development Program of China (2016YFC1302300), Guangdong Science and Technology Department (2016B030229004, 2016A020216028), Guangzhou Science Technology and Innovation Commission (201803040015).

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Author notes

  1. Yujie Liu and Huaqin Zheng have contributed equally to this work.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Yujie Liu, Qian Li, Shunying Li, Hongna Lai & Erwei Song

  2. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Yujie Liu, Qian Li, Shunying Li, Hongna Lai & Erwei Song

  3. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou University City, 132 Waihuan East Road, Guangzhou, 510006, China

    Huaqin Zheng & Ding Li

  4. Department of Medical Oncology, No. 2 Affiliated Hospital, Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China

    Jingqi Chen

  5. Translational Medicine Center, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China

    Jingqi Chen

Authors
  1. Yujie Liu
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  2. Huaqin Zheng
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  3. Qian Li
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  4. Shunying Li
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  7. Ding Li
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Contributions

YL, ES, JC and DL conceived and designed the experiments. YL and HZ equally did the experiment. QL, SL and HL provide animal experiment guide and management. JC and DL are co-PI and supervisor for this research.

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Correspondence to Ding Li or Jingqi Chen.

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Liu, Y., Zheng, H., Li, Q. et al. Discovery of CCL18 antagonist blocking breast cancer metastasis. Clin Exp Metastasis 36, 243–255 (2019). https://doi.org/10.1007/s10585-019-09965-2

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  • DOI: https://doi.org/10.1007/s10585-019-09965-2

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