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Identifying the organ\u2010specific molecular determinants of EVs can develop potential anti\u2010metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer\u2010derived EVs, are found to play a crucial role in facilitating bone\u2010tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre\u2010metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP\u2010associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker <jats:italic>\u03b1<\/jats:italic>V\u2010integrin. VAPA\u2010enriched LOs\u2010induced pre\u2010metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs\u2010delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott\u2013Aldrich syndrome protein (N\u2010WASP) via dual mechanisms, consequently resulting in ARP2\/3 complex\u2010mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N\u2010WASP inhibitor 187\u20101\u2010packaged LOs (LOs\/187\u20101) dramatically abolishes the inductive effect of VAPA\u2010enriched LOs on pre\u2010metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone\u2010tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.<\/jats:p>","DOI":"10.1002\/advs.202201974","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T06:44:58Z","timestamp":1664347498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Large Oncosome\u2010Loaded VAPA Promotes Bone\u2010Tropic Metastasis of Hepatocellular Carcinoma Via Formation of Osteoclastic Pre\u2010Metastatic Niche"],"prefix":"10.1002","volume":"9","author":[{"given":"Shuxia","family":"Zhang","sequence":"first","affiliation":[{"name":"Program of Cancer Research Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology Affiliated Guangzhou Women and Children's Hospital School of Basic Medical Sciences Guangzhou Medical University  Guangzhou 510623 P. R. 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