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To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity\u2010related genes to measure E\/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan\u2013Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1<jats:sup>bright<\/jats:sup>\u2010cells identified high\u2010grade PMP, and discriminated solid masses from ascitic\/mucin\u2010embedded tumor cells in both forms of PM. Epithelial\/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (<jats:italic>p<\/jats:italic>\u2009=\u2009.0343 and <jats:italic>p<\/jats:italic>\u2009=\u2009.0339, respectively, log\u2010rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E\/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.<\/jats:p>","DOI":"10.1002\/ijc.35137","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T19:04:57Z","timestamp":1723748697000},"page":"201-215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Stemness and hybrid epithelial\u2010mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei"],"prefix":"10.1002","volume":"156","author":[{"given":"Nayana","family":"Lazzari","sequence":"first","affiliation":[{"name":"Immunology and Molecular Oncology Veneto Institute of Oncology IOV \u2013 IRCCS  Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Rigotto","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Oncology Veneto Institute of Oncology IOV \u2013 IRCCS  Padua 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