{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T23:58:20Z","timestamp":1781654300188,"version":"3.54.5"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is an aggressive cancer of the pleural lining, primarily associated with asbestos exposure. Despite advancements in multimodal treatment, patient survival remains poor. Epithelial\u2013mesenchymal transition (EMT) has emerged as a crucial process driving MPM pathogenesis, metastasis, and resistance to therapy. This review explores the molecular mechanisms underlying EMT in MPM, including key signaling pathways such as TGF-\u03b2, Wnt\/\u03b2-catenin, and PI3K\/Akt. We also discuss the diagnostic and prognostic significance of EMT-related biomarkers and emerging targeted therapies aimed at reversing EMT or exploiting EMT-induced vulnerabilities. Additionally, recent clinical trials, including the MARS 2 trial, are reviewed to provide insight into the evolving treatment landscape.<\/jats:p>","DOI":"10.3390\/cells14080585","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T09:06:51Z","timestamp":1744621611000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Role of Epithelial\u2013Mesenchymal Transition in Malignant Pleural Mesothelioma: From Pathogenesis to Diagnosis and Treatment"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5417-6392","authenticated-orcid":false,"given":"Dimitrios E.","family":"Magouliotis","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Minervini","sequence":"additional","affiliation":[{"name":"Luzern Kanton Hospital, 6000 Luzern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5321-5828","authenticated-orcid":false,"given":"Ugo","family":"Cioffi","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde","family":"De Simone","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Patrini","sequence":"additional","affiliation":[{"name":"University College of London Hospital, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4459-7721","authenticated-orcid":false,"given":"Marco","family":"Scarci","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Hammersmith Hospital, Imperial College Healthcare, National Health Service (NHS) Trust, London W2 1NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ramundo, V., Zanirato, G., and Aldieri, E. (2021). The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212216"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.ejcts.2009.08.027","article-title":"Prognostic significance of epithelial-mesenchymal transition in malignant pleural mesothelioma","volume":"37","author":"Schramm","year":"2010","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1089\/ars.2009.2737","article-title":"Epithelial-mesenchymal transition: From molecular mechanisms, redox regulation to implications in human health and disease","volume":"12","author":"Cannito","year":"2010","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Celi\u00e0-Terrassa, T., and Kang, Y. (2024). How important is EMT for cancer metastasis?. PLoS Biol., 22.","DOI":"10.1371\/journal.pbio.3002487"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13045-022-01347-8","article-title":"The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis","volume":"15","author":"Huang","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.devcel.2021.02.028","article-title":"Epithelial plasticity, epithelial-mesenchymal transition, and the TGF-\u03b2 family","volume":"56","author":"Katsuno","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41580-018-0080-4","article-title":"New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer","volume":"20","author":"Dongre","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000356874","article-title":"Clinical significance of epithelial-mesenchymal transition-associated markers in malignant pleural mesothelioma","volume":"86","author":"Iwanami","year":"2014","journal-title":"Oncology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tsubakihara, Y., and Moustakas, A. (2018). Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor \u03b2. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113672"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e31756","DOI":"10.7554\/eLife.31756","article-title":"TGF-\u03b2 uses a novel mode of receptor activation to phosphorylate SMAD1\/5 and induce epithelial-to-mesenchymal transition","volume":"7","author":"Ramachandran","year":"2018","journal-title":"Elife"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s12272-018-01108-7","article-title":"Therapeutic implications of cancer epithelial-mesenchymal transition (EMT)","volume":"42","author":"Cho","year":"2019","journal-title":"Arch. Pharm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/1759-7714.13784","article-title":"Functional inhibition of heat shock protein 70 by VER-155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism","volume":"12","author":"Sakai","year":"2021","journal-title":"Thorac. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Albakova, Z., Armeev, G.A., Kanevskiy, L.M., Kovalenko, E.I., and Sapozhnikov, A.M. (2020). HSP70 Multi-Functionality in Cancer. Cells., 9.","DOI":"10.3390\/cells9030587"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.7314\/APJCP.2013.14.6.3625","article-title":"Hydrogen peroxide promotes epithelial to mesenchymal transition and stemness in human malignant mesothelioma cells","volume":"14","author":"Kim","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41698-024-00627-5","article-title":"NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity","volume":"8","author":"Xu","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0463.2012.02931.x","article-title":"Expression of snail, twist, and Zeb1 in malignant mesothelioma","volume":"121","author":"Merikallio","year":"2013","journal-title":"APMIS"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wu, L., Amjad, S., Yun, H., Mani, S., and de Perrot, M. (2022). A panel of emerging EMT genes identified in malignant mesothelioma. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-04973-x"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kim, M.-C., Hwang, S.-H., Kim, N.-Y., Lee, H.-S., Ji, S., Yang, Y., and Kim, Y. (2018). Hypoxia promotes acquisition of aggressive phenotypes in human malignant mesothelioma. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4720-z"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41392-024-02121-7","article-title":"AXL signaling in cancer: From molecular insights to targeted therapies","volume":"10","author":"Yadav","year":"2025","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5522","DOI":"10.1038\/onc.2017.147","article-title":"E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells","volume":"36","author":"Kato","year":"2017","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00109-018-1725-7","article-title":"The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma","volume":"97","author":"Laszlo","year":"2019","journal-title":"J. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yuen, M.L., Zhuang, L., Rath, E.M., Yu, T., Johnson, B., Sarun, K.H., Wang, Y., Kao, S., Linton, A., and Clarke, C.J. (2021). The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910225"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bai, Y., Wang, X., Hou, J., Geng, L., Liang, X., Ruan, Z., Guo, H., Nan, K., and Jiang, L. (2020). Identification of a Five-Gene Signature for Predicting Survival in Malignant Pleural Mesothelioma Patients. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.00899"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1165\/rcmb.2009-0060OC","article-title":"MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications","volume":"42","author":"Busacca","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"330","DOI":"10.4161\/cbt.19073","article-title":"MiRNA-21: A biomarker predictive for platinum-based adjuvant chemotherapy response in patients with non-small cell lung cancer","volume":"13","author":"Gao","year":"2012","journal-title":"Cancer Biol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.annonc.2020.07.009","article-title":"Clinical development of therapies targeting TGF\u03b2: Current knowledge and future perspectives","volume":"31","author":"Ciardiello","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_28","unstructured":"Oncotelic Therapeutics (2025, March 11). Oncotelic Therapeutics. A TGF-Beta Company-Oncotelic. Published 2022. Available online: https:\/\/www.oncotelic.com\/wp-content\/uploads\/2022\/01\/TGF-beta-PresentationRev5-Final.pdf."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1200\/JCO.2018.79.0543","article-title":"Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND\u2014A double-blind, randomized, phase II study","volume":"37","author":"Fennell","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.jtho.2018.06.011","article-title":"Scientific advances and new frontiers in mesothelioma therapeutics","volume":"13","author":"Mutti","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yun, K.M., and Bazhenova, L. (2024). Emerging New Targets in Systemic Therapy for Malignant Pleural Mesothelioma. Cancers, 16.","DOI":"10.3390\/cancers16071252"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bertoli, E., De Carlo, E., Bortolot, M., Stanzione, B., Del Conte, A., Spina, M., and Bearz, A. (2024). Targeted Therapy in Mesotheliomas: Uphill All the Way. Cancers, 16.","DOI":"10.3390\/cancers16111971"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41392-022-01221-6","article-title":"Histone deacetylase inhibitors promote breast cancer metastasis by elevating NEDD9 expression","volume":"8","author":"Hu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.jtho.2017.05.024","article-title":"Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma","volume":"12","author":"Kao","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"144888","DOI":"10.1016\/j.gene.2020.144888","article-title":"Immunomodulatory role for MicroRNAs: Regulation of PD-1\/PD-L1 and CTLA-4 immune checkpoints expression","volume":"754","author":"Skafi","year":"2020","journal-title":"Gene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1186\/s13046-020-01783-9","article-title":"HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer","volume":"39","author":"Hu","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label, phase 3 trial","volume":"397","author":"Baas","year":"2021","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0140-6736(21)00882-5","article-title":"Heterogeneity of treatment effects in malignant pleural mesothelioma","volume":"398","author":"Tagliamento","year":"2021","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Borgeaud, M., Kim, F., Friedlaender, A., Lococo, F., Addeo, A., and Minervini, F. (2023). The Evolving Role of Immune-Checkpoint Inhibitors in Malignant Pleural Mesothelioma. J. Clin. Med., 12.","DOI":"10.3390\/jcm12051757"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e057663","DOI":"10.1136\/bmjopen-2021-057663","article-title":"Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial","volume":"12","author":"Kok","year":"2022","journal-title":"BMJ Open"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1172\/JCI39104","article-title":"The basics of epithelial-mesenchymal transition","volume":"119","author":"Kalluri","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2008.07.001","article-title":"TGFbeta in Cancer","volume":"134","year":"2008","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1158\/0008-5472.CAN-12-1223","article-title":"Microenvironmental regulation of epithelial-mesenchymal transitions in cancer","volume":"72","author":"Gao","year":"2012","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S2213-2600(24)00119-X","article-title":"Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): A phase 3 randomised controlled trial","volume":"12","author":"Lim","year":"2024","journal-title":"Lancet Respir. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jtho.2024.12.014","article-title":"A Perspective on the MARS2 Trial","volume":"20","author":"Lim","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13073-021-00931-w","article-title":"Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma","volume":"13","author":"Meiller","year":"2021","journal-title":"Genome Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/s41467-019-09307-6","article-title":"Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications","volume":"10","author":"Blum","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/8\/585\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:13:15Z","timestamp":1760029995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/8\/585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,12]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["cells14080585"],"URL":"https:\/\/doi.org\/10.3390\/cells14080585","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,12]]}}}