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Myeloid-derived suppressor cells promote lung cancer metastasis by CCL11 to activate ERK and AKT signaling and induce epithelial-mesenchymal transition in tumor cells

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Abstract

Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune activities and facilitate cancer progression. Although the concept of immunosuppressive MDSCs is well established, the mechanism that MDSCs regulate non-small cell lung cancer (NSCLC) progression through the paracrine signals is still lacking. Here, we reported that the infiltration of MDSCs within NSCLC tissues was associated with the progression of cancer status, and was positively correlated with the Patient-derived xenograft model establishment, and poor patient prognosis. Intratumoral MDSCs directly promoted NSCLC metastasis and highly expressed chemokines that promote NSCLC cells invasion, including CCL11. CCL11 was capable of activating the AKT and ERK signaling pathways to promote NSCLC metastasis through the epithelial-mesenchymal transition (EMT) process. Moreover, high expression of CCL11 was associated with a poor prognosis in lung cancer as well as other types of cancer. Our findings underscore that MDSCs produce CCL11 to promote NSCLC metastasis via activation of ERK and AKT signaling and induction of EMT, suggesting that the MDSCs-CCL11-ERK/AKT-EMT axis contains potential targets for NSCLC metastasis treatment.

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Fig. 1: Gene expression profiles associated with NSCLC metastasis and PDX model engraftment.
Fig. 2: MDSCs enhance NSCLC metastasis.
Fig. 3: Tumoral MDSCs having high expression of CCL11 could induce NSCLC cell invasion.
Fig. 4: CCL11 promotes NSCLC metastasis.
Fig. 5: AKT and ERK signaling pathways may be involved in CCL11-mediated NSCLC metastasis.
Fig. 6: AKT and ERK signaling pathways are involved in CCL11-mediated NSCLC metastasis.

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Data availability

RNA-Seq of human NSCLC samples, MDSCs and A549 cells have been uploaded to public databases (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE136949). Other data generated or analyzed during this study are included either in this article or in the supplementary information files.

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Acknowledgements

We thank the cancer patients who donated their tissues. This work was supported by Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19030205); and National Key Research and Development Plan (2017YFE0131600, 2019YFA0111500); and National Natural Science Foundation of China (81961128003; 81972672; 31872800; 81773301; 82003054); and China Postdoctoral Science Foundation (2018M640771); and Guangdong Provincial Significant New Drugs Development (2019B020202003); and Guangdong Basic and Applied Basic Research Foundation (2019A1515110084, 2019A1515010062, 2020A1515011516); and Guangdong Special Support Program (2017TX04R102); and Science and Technology Planning Project of Guangdong Province (2017B030314056); and Natural Science Foundation of Guangdong Province (2020A0505100062); and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (2017B030314120); and Guangzhou City Science and Technology Key Topics Project (201904020025); and Guangzhou Science and Technology Plan Project (201907010042, 201904010473) and Foundation of Guangzhou Science and Information Technology of Guangzhou Key Project (201803040009); and Guangzhou Regenerative Medicine and Health Guangdong Laboratory Frontier Research Program (2018GZR110105003); and Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR0201002); and Research Program of the Hefei Institute of Stem Cell and Regenerative Medicine (2019YF001); and Science and Technology Program of Guangzhou (202002020083).

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Author notes

  1. These authors contributed equally: Shouheng Lin, Xuchao Zhang, Guohua Huang, Lin Cheng

Authors and Affiliations

  1. Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    Shouheng Lin & Xiaofang Sun

  2. State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Shouheng Lin, Lin Cheng, Jiang Lv, Diwei Zheng, Simiao Lin, Suna Wang, Qiting Wu, Youguo Long, Duanqing Pei, Peng Li & Yao Yao

  3. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China

    Shouheng Lin, Lin Cheng, Duanqing Pei, Peng Li & Xiaofang Sun

  4. Guangdong Lung Cancer Institute, Medical Research Center, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Xuchao Zhang & Yilong Wu

  5. Department of Respiratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Guohua Huang

  6. Hunan Zhaotai Biopharmaceutical Co., Ltd, Changsha, China

    Baiheng Li

  7. Guangdong Cord Blood Bank, Guangzhou, Guangdong, China

    Wei Wei

  8. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, Stem Cell and Regenerative Medicine Centre, University of Hong Kong, Hong Kong, China

    Pentao Liu

  9. Institute of Hematology, Medical College, Jinan University, Guangzhou, China

    Yangqiu Li

  10. Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Zhesheng Wen

  11. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China

    Shuzhong Cui

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  1. Shouheng Lin
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  19. Xiaofang Sun
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Contributions

SL and LC, contributed to the conception and design; the collection and/or assembly of data; data analysis and interpretation; and manuscript writing. XZ, GH, JL, and DZ contributed to the provision of study material or patient samples and the collection and/or assembly of data. BL, SL, SW, YL, and QW provided animal care and administrative support. WW, PL, DP, YY, SZC, ZW, and SC contributed to the conception and design of the study. XS, YY, YL, and PL contributed to the conception and design of the study; data analysis and interpretation; manuscript writing; and the final approval of the manuscript and provided financial support. All authors read and approved the final manuscript.

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Correspondence to Xiaofang Sun, Yilong Wu or Yao Yao.

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Lin, S., Zhang, X., Huang, G. et al. Myeloid-derived suppressor cells promote lung cancer metastasis by CCL11 to activate ERK and AKT signaling and induce epithelial-mesenchymal transition in tumor cells. Oncogene 40, 1476–1489 (2021). https://doi.org/10.1038/s41388-020-01605-4

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