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ZIM3 activation of CCL25 expression in pulmonary metastatic nodules of osteosarcoma recruits M2 macrophages to promote metastatic growth

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Abstract

Tumor-associated macrophages (TAMs) play an important role in tumor growth and metastasis. However, the involvement of TAMs infiltration in pulmonary osteosarcoma (OS) metastasis remains poorly understood. Therefore, the effect of OS cells on macrophages migration was investigated by in vivo and in vitro experiments to evaluate the infiltration and mechanism of TAMs in pulmonary OS metastases. The results showed that the zinc finger protein ZIM3 was upregulated in OS cells than in osteoblasts and activated the expression of CCL25, which subsequently promoted the migration of M2 macrophages. CCL25 or ZIM3 silencing in OS cells inhibited the infiltration of M2 macrophages and the formation of pulmonary metastatic nodules in a mouse model of pulmonary OS metastasis and prolonged the survival of the mice. Furthermore, bioinformatics analyses revealed that CCL25 and ZIM3 expressions are negatively correlated with the prognosis of OS patients. In conclusion, this study found that a large number of M2 TAMs were recruited into pulmonary metastatic nodules of OS through the activation of the ZIM3-CCL25 axis in OS cells, thereby facilitating OS metastasis. Therefore, the suppression of ZIM3-CCL25-induced recruitment of M2 TAMs to the metastatic sites might be considered as a therapeutic approach to inhibit the growth of pulmonary OS metastases.

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Funding

This work was supported by the Shaanxi Province Innovation Talent Promotion Program, Youth Science and Technology Star Project (grant number: 2020KJXX-028) and the National Program on Key Research and Development Project of China (grant number: 2018YFE0114200).

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  1. Jing Li and Chenguang Zhao have contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, People’s Republic of China

    Jing Li, Dong Wang, Yubing Yang, Jiaxi Li, Feng Cui, Xijing He & Jie Qin

  2. Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China

    Chenguang Zhao

  3. Institute of Photonics and Photon-Technology, Northwest University, Xi’an, Shaanxi Province, People’s Republic of China

    Shuang Wang

  4. Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China

    Hui Dong

  5. School of Life Science and Technology, Xidian University, Xi’an, Shaanxi Province, People’s Republic of China

    Difan Wang

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  1. Jing Li
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Contributions

JL contributed to conceptualization, methodology, software, validation, formal analysis, investigation, writing the original draft, writing, reviewing and editing; CZ contributed to conceptualization, methodology, validation, formal analysis, writing, reviewing and editing; DW performed data curation; SW carried out formal analysis; DW contributed to investigation and resources; FC provided software; YY contributed to methodology and validation; JL contributed to formal analysis and resources; XH was involved in conceptualization, project administration, and funding acquisition; JQ contributed to conceptualization, methodology, writing, reviewing and editing, project administration, and funding acquisition.

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Correspondence to Xijing He or Jie Qin.

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Li, J., Zhao, C., Wang, D. et al. ZIM3 activation of CCL25 expression in pulmonary metastatic nodules of osteosarcoma recruits M2 macrophages to promote metastatic growth. Cancer Immunol Immunother 72, 903–916 (2023). https://doi.org/10.1007/s00262-022-03300-7

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