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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,9,26]]},"abstract":"<jats:p>\n                    Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of\n                    <jats:italic>TNF\u03b1<\/jats:italic>\n                    . Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive\/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (\n                    <jats:italic>Hmgb1<\/jats:italic>\n                    <jats:sup>\u0394pMeso<\/jats:sup>\n                    ) and the conditional myelomonocytic-lineage HMGB1-knockout (\n                    <jats:italic>Hmgb1<\/jats:italic>\n                    <jats:sup>\u0394Mylc<\/jats:sup>\n                    ) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that\n                    <jats:italic>Hmgb1<\/jats:italic>\n                    <jats:sup>\u0394pMeso<\/jats:sup>\n                    , whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of\n                    <jats:italic>TNF\u03b1<\/jats:italic>\n                    . Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings,\n                    <jats:italic>Hmgb1<\/jats:italic>\n                    <jats:sup>\u0394pMeso<\/jats:sup>\n                    mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2307999120","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T13:31:57Z","timestamp":1695216717000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":32,"title":["HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma"],"prefix":"10.1073","volume":"120","author":[{"given":"Joelle S.","family":"Suarez","sequence":"first","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3746-7478","authenticated-orcid":false,"given":"Flavia","family":"Novelli","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Goto","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"},{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8798-4142","authenticated-orcid":false,"given":"Michiko","family":"Ehara","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, Division of Oral Pathogenesis and Disease Control, School of Dentistry, Asahi University, Mizuho Gifu 501-0296, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Steele","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0818-9632","authenticated-orcid":false,"given":"Alicia A.","family":"Zolondick","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"},{"name":"Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI 96822"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Xue","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"},{"name":"John A. Burns, School of Medicine, University of Hawai\u2019i, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9842-2628","authenticated-orcid":false,"given":"Ronghui","family":"Xu","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Saito","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-1065","authenticated-orcid":false,"given":"Sandra","family":"Pastorino","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 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96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Wakeham","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Berger","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3222-3471","authenticated-orcid":false,"given":"Harvey I.","family":"Pass","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, New York University, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Gaudino","sequence":"additional","affiliation":[{"name":"Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 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Tang R. Kang H. J. Zeh M. T. Lotze The multifunctional protein HMGB1: 50 years of discovery. Nat. Rev. Immunol. 10.1038\/s41577-023-00894-6 (2023).","DOI":"10.1038\/s41577-023-00894-6"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.37.11.803"},{"key":"e_1_3_4_40_2","first-page":"L84","article-title":"Contrasting effects of alveolar macrophages and neutrophils on asbestos-induced pulmonary epithelial cell injury","volume":"266","author":"Kamp D. W.","year":"1994","unstructured":"D. W. Kamp, M. M. Dunn, J. S. Sbalchiero, A. M. Knap, S. A. Weitzman, Contrasting effects of alveolar macrophages and neutrophils on asbestos-induced pulmonary epithelial cell injury. Am. J. Physiol. 266, L84\u201391 (1994).","journal-title":"Am. J. 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