Stemness and hybrid epithelial‐mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei

• Published in: International journal of cancer 2025-01, Vol.156 (1), p.201-215
• Main Authors: Lazzari, Nayana, Rigotto, Giulia, Montini, Barbara, Del Bianco, Paola, Moretto, Elena, Palladino, Federica, Cappellesso, Rocco, Tonello, Marco, Cenzi, Carola, Scapinello, Antonio, Piano, Maria Assunta, Rossi, Carlo Riccardo, Dalerba, Piero, Pilati, Pierluigi, Sommariva, Antonio, Calabrò, Maria Luisa
• Format: Article
• Language: English
• Subjects: Acetylsalicylic acid; Adult; Aged; Aldehyde dehydrogenase; Aldehyde Dehydrogenase 1 Family - genetics; Aldehyde Dehydrogenase 1 Family - metabolism; cancer stem cells; Chemotherapy; Cisplatin; Colorectal carcinoma; CRS‐HIPEC; Epithelial-Mesenchymal Transition; epithelial‐mesenchymal plasticity; Female; Humans; Hyperthermic Intraperitoneal Chemotherapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; malignant mesothelioma; Mesothelioma; Mesothelioma - genetics; Mesothelioma - pathology; Mesothelioma, Malignant - pathology; Metastases; Middle Aged; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Peritoneal Neoplasms - pathology; Peritoneal Neoplasms - secondary; Peritoneum; Pluripotency; Prognosis; pseudomyxoma peritonei; Pseudomyxoma Peritonei - metabolism; Pseudomyxoma Peritonei - pathology; Regression analysis; Retinal Dehydrogenase - genetics; Retinal Dehydrogenase - metabolism; Sensitivity analysis; Tumor cells; Tumor Cells, Cultured; Tumors
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.35137

Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial‐mesenchymal (E/M) axis. 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‐related 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–Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright‐cells identified high‐grade PMP, and discriminated solid masses from ascitic/mucin‐embedded 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 (p = .0343 and p = .0339, respectively, log‐rank 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. What's new? Factors involved in peritoneal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) are poorly characterized. Increased amounts of cancer stem cells identified high‐grade PMP and distinguished mass‐derived from ascitic/mucin‐associated cells in MM and PMP. Epithelial/early hybrid EMT scores and a hybrid profile linked to pluripotency factors were significantly associated with early progression. A stemness modifier decreased spheroid formation and chemoresistance in primary cultures. Combining chemotherapy with stemness modulators might counteract resistance in these patients.