{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T22:54:05Z","timestamp":1765234445470,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:00:00Z","timestamp":1574121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero della Salute, Ricerca Finalizzata 2009 (RF-2009-1546664, MD)","award":["RF-2009-1546664"],"award-info":[{"award-number":["RF-2009-1546664"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background\u2014There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method\u2014We analyzed a series of 22 na\u00efve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy (\u201cprogressed\u201d). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results\u2014In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two \u201cprogressed\u201d DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a \u201cprogressed\u201d DMPM. Conclusion\u2014The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR\/HER2 and HER3 and of Axl and MET deserves further investigation.<\/jats:p>","DOI":"10.3390\/ijms20225817","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T11:30:17Z","timestamp":1574163017000},"page":"5817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-6382","authenticated-orcid":false,"given":"Antonino","family":"Belfiore","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5808-0387","authenticated-orcid":false,"given":"Adele","family":"Busico","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Bozzi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Brich","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Dallera","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Conca","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iolanda","family":"Capone","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7226-1942","authenticated-orcid":false,"given":"Annunziata","family":"Gloghini","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8306-6851","authenticated-orcid":false,"given":"Chiara C.","family":"Volpi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonello D.","family":"Cabras","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvana","family":"Pilotti","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5442-2642","authenticated-orcid":false,"given":"Dario","family":"Baratti","sequence":"additional","affiliation":[{"name":"Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8194-9810","authenticated-orcid":false,"given":"Marcello","family":"Guaglio","sequence":"additional","affiliation":[{"name":"Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Deraco","sequence":"additional","affiliation":[{"name":"Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeki","family":"Kusamura","sequence":"additional","affiliation":[{"name":"Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Perrone","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1245\/s10434-014-3978-x","article-title":"Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritonealmesothelioma: A systematic review and meta-analysis","volume":"22","author":"Helm","year":"2015","journal-title":"Ann. 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