TY - JOUR
T1 - Stemness and hybrid epithelial-mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei
AU - Lazzari, Nayana
AU - Rigotto, Giulia
AU - Montini, Barbara
AU - Del Bianco, Paola
AU - Moretto, Elena
AU - Palladino, Federica
AU - Cappellesso, Rocco
AU - Tonello, Marco
AU - Cenzi, Carola
AU - Scapinello, Antonio
AU - Piano, Maria Assunta
AU - Rossi, Carlo Riccardo
AU - Dalerba, Piero
AU - Pilati, Pierluigi
AU - Sommariva, Antonio
AU - Calabrò, Maria Luisa
N1 - Publisher Copyright: © 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - 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.
AB - 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.
KW - CRS-HIPEC
KW - cancer stem cells
KW - epithelial-mesenchymal plasticity
KW - malignant mesothelioma
KW - pseudomyxoma peritonei
UR - http://www.scopus.com/inward/record.url?scp=85201256075&partnerID=8YFLogxK
U2 - 10.1002/ijc.35137
DO - 10.1002/ijc.35137
M3 - Article
C2 - 39146488
SN - 0020-7136
VL - 156
SP - 201
EP - 215
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 1
ER -