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The UDP/P2y6 axis promotes lung metastasis of melanoma by remodeling the premetastatic niche

Cellular & Molecular Immunology volume 17, pages 1269–1271 (2020)Cite this article

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Tumor metastasis is the major cause of death in cancer patients, in which tumor cells progressively migrate from a primary site to distant organs. Although there are multiple steps in the tumor metastatic process, growing evidence indicates that one vital step in metastasis is paracrine alteration of distant tissues by the primary tumor, allowing metastatic colonization of an area hospitable to the cancer cells, termed the premetastatic niche,1 which is consistent with the “seed and soil” hypothesis. In this case, prometastatic tumor cells (“seeds”) colonize the metastatic tissue (“congenial soil”) in which the microenvironment has been altered by diverse signaling molecules to modulate cellular components, especially bone marrow-derived immune cells.2,3,4 It is well known that the nucleotide signaling network plays an important role in inflammation and the tumor microenvironment by regulating various immune cells.5,6 Extracellular nucleosides (adenosine) and nucleotides (ATP, ADP, UTP, UDP, and sugar UDP) function as signaling molecules by activating nucleotide receptors, including P1 receptors and P2 receptors. The purinergic P2 receptors are divided into ionotropic P2X receptors and metabotropic P2Y receptors, which are members of the G-protein-coupled receptor family.7 Our previous study showed that chemotherapy-induced extracellular UDP release can activate the P2y6 receptor on breast tumor cells to facilitate breast cancer metastasis.8 However, the role and mechanism of UDP/P2y6 signaling in the premetastatic immune microenvironment during the tumor metastatic process is poorly understood.

Next, to further determine whether the reduction in tumor metastasis by P2y6 deficiency is dependent on hematopoietic cells, a bone marrow transplantation experiment was carried out. We analyzed metastatic lung tumor nodules and found that P2y6 contributed to melanoma B16F10 metastasis by prominently regulating hematopoietic cells (Fig. 1g). Therefore, to investigate the potential role of immune cells in metastasis, we analyzed tumor-initiating immune cell propagation in the premetastatic niche in the lungs of B16F10 tumor-bearing mice. When the volumes of subcutaneous B16F10 tumors reached 400–500 mm3, we analyzed the lung bronchoalveolar lavage fluid and tissues of mice, and flow cytometry revealed that the infiltration of neutrophils was significantly reduced in P2y6KO mice compared with WT mice, while the infiltration of other immune cells, including macrophages, natural killer cells, dendritic cells and T cells, was only slightly changed (Fig. 1h, i). Moreover, both immunohistochemistry anti-MPO (myeloperoxidase) staining and immunofluorescence anti-Ly6G staining showed that P2y6 loss strikingly decreased neutrophil infiltration in the lungs (Fig. 1j), which altered the premetastatic niche. This finding provides strong evidence for the role of neutrophils in promoting tumor metastasis.10

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Acknowledgements

This work was supported in part by grants from the National Key R&D Program of China (2018YFA0507001); National Natural Science Foundation of China (81672811, 31770969, 81871250, 81830083 and 81902892); Shanghai Super Postdoctoral Incentive Program; China Postdoctoral Science Foundation (2018M640364); Shanghai Sailing Program (19YF1414400); and Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-05-E00011).

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  1. These authors contributed equally: Juliang Qin, Zhen Zhang

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  1. Shanghai Key Laboratory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Juliang Qin, Zhen Zhang, Zhixiang Fu, Hua Ren, Mingyao Liu, Min Qian & Bing Du

  2. Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600, Nanfeng Road, Fengxian District, Shanghai, 201499, China

    Juliang Qin

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Correspondence to Bing Du.

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Qin, J., Zhang, Z., Fu, Z. et al. The UDP/P2y6 axis promotes lung metastasis of melanoma by remodeling the premetastatic niche. Cell Mol Immunol 17, 1269–1271 (2020). https://doi.org/10.1038/s41423-020-0392-0

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