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Development of supportive metastatic microenvironments, referred to as premetastatic niches (PMNs), in certain distant organs before arrival of metastatic cells, is critical in metastasis. However, the mechanisms of PMN formation are not fully clear. Here, we demonstrated that chemoattractant C\u2013C motif chemokine ligand 2 (CCL2) could be stimulated by heat shock protein 60 (HSP60) on the surface of murine 4\u2009T1 breast cancer cell\u2013released LC3\n                    <jats:sup>+<\/jats:sup>\n                    extracellular vesicles (LC3\n                    <jats:sup>+<\/jats:sup>\n                    EVs) via the TLR2\u2010MyD88\u2010NF\u2010\u03baB signal cascade in lung fibroblasts, which subsequently promoted lung PMN formation through recruiting monocytes and suppressing T cell function. Consistently, reduction of LC3\n                    <jats:sup>+<\/jats:sup>\n                    EV release or HSP60 level or neutralization of CCL2 markedly attenuated PMN formation and lung metastasis. Furthermore, the number of circulating LC3\n                    <jats:sup>+<\/jats:sup>\n                    EVs and HSP60 level on LC3\n                    <jats:sup>+<\/jats:sup>\n                    EVs in the plasma of breast cancer patients were positively correlated with disease progression and lung metastasis, which might have potential value as biomarkers of lung metastasis in breast cancer patients (AUC\u00a0=\u00a00.898, 0.694, respectively). These findings illuminate a novel mechanism of PMN formation and might provide therapeutic targets for anti\u2010metastasis therapy for patients with breast cancer.\n                  <\/jats:p>","DOI":"10.1111\/cas.15507","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T23:05:00Z","timestamp":1658790300000},"page":"3405-3416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Tumor cell\u2013released\n                    <scp>LC3<\/scp>\n                    \u2010positive\n                    <scp>EVs<\/scp>\n                    promote lung metastasis of breast cancer through enhancing premetastatic niche formation"],"prefix":"10.1111","volume":"113","author":[{"given":"Xiaotong","family":"Sun","sequence":"first","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing 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Immunology Medical School of Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6136-8867","authenticated-orcid":false,"given":"Fang","family":"Huang","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Wei","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifa","family":"Wen","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing 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Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Shen","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlang","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Zhongda Hospital Medical School of Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Pan","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Department of Immunology Medical School of Southeast University  Nanjing 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