{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:51:40Z","timestamp":1793055100538,"version":"4.5.0"},"reference-count":78,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universit\u00e0 del Piemonte Orientale","award":["Fondi ricerca locale 2016"],"award-info":[{"award-number":["Fondi ricerca locale 2016"]}]},{"name":"Universit\u00e0 del Piemonte Orientale","award":["fondi Ricerca locale 2020"],"award-info":[{"award-number":["fondi Ricerca locale 2020"]}]},{"name":"Fondazione Umberto Veronesi","award":["CoVIBD"],"award-info":[{"award-number":["CoVIBD"]}]},{"name":"HERMES (HEreditary Risk in MESothelioma) project.","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes\u2019 recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.<\/jats:p>","DOI":"10.3390\/ijms22094391","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T13:59:14Z","timestamp":1619099954000},"page":"4391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4517-9051","authenticated-orcid":false,"given":"Silvia","family":"Mola","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"},{"name":"Center for Translational Research on Autoimmune &amp; Allergic Diseases (CAAD), Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Pinton","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1922-0818","authenticated-orcid":false,"given":"Marco","family":"Erreni","sequence":"additional","affiliation":[{"name":"Unit of Advanced Optical Microscopy, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6246-5968","authenticated-orcid":false,"given":"Marco","family":"Corazzari","sequence":"additional","affiliation":[{"name":"Center for Translational Research on Autoimmune &amp; Allergic Diseases (CAAD), Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"},{"name":"Department of Health Sciences, University of Piemonte Orientale \u201cA. Avogadro\u201d, 28100 Novara, Italy"},{"name":"Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-5783","authenticated-orcid":false,"given":"Marco","family":"De Andrea","sequence":"additional","affiliation":[{"name":"Center for Translational Research on Autoimmune &amp; Allergic Diseases (CAAD), Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"},{"name":"Department of Public Health and Pediatric Sciences, Medical School, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambra A.","family":"Grolla","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Martini","sequence":"additional","affiliation":[{"name":"Center for Translational Research on Autoimmune &amp; Allergic Diseases (CAAD), Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"},{"name":"Department of Translational Medicine (DIMET), University of Piemonte Orientale \u201cA. Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7183-5561","authenticated-orcid":false,"given":"Chiara","family":"Porta","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"},{"name":"Center for Translational Research on Autoimmune &amp; Allergic Diseases (CAAD), Universit\u00e0 del Piemonte Orientale \u201cAmedeo Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.jtho.2017.05.011","article-title":"Comprehensive Analysis of the Discordance of EGFR Mutation Status between Tumor Tissues and Matched Circulating Tumor DNA in Advanced Non\u2013Small Cell Lung Cancer","volume":"12","author":"Wan","year":"2017","journal-title":"J. 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