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

Author:

Lazzari Nayana1,Rigotto Giulia1,Montini Barbara1,Del Bianco Paola2,Moretto Elena1,Palladino Federica1,Cappellesso Rocco3,Tonello Marco4,Cenzi Carola24,Scapinello Antonio5,Piano Maria Assunta1,Rossi Carlo Riccardo6,Dalerba Piero7,Pilati Pierluigi4,Sommariva Antonio468,Calabrò Maria Luisa1ORCID

Affiliation:

1. Immunology and Molecular Oncology Veneto Institute of Oncology IOV – IRCCS Padua Italy

2. Clinical Research Unit Veneto Institute of Oncology IOV – IRCCS Padua Italy

3. Pathological Anatomy Unit Padua University Hospital Padua Italy

4. Surgical Oncology of the Esophagus and Digestive Tract Veneto Institute of Oncology IOV – IRCCS Padua Italy

5. Anatomy and Histopathology Veneto Institute of Oncology IOV – IRCCS Padua Italy

6. Surgical Oncology Veneto Institute of Oncology IOV – IRCCS Padua Italy

7. Center for Discovery and Innovation (CDI) Hackensack Meridian School of Medicine Nutley New Jersey USA

8. Advanced Surgical Oncology Unit, Surgical Oncology of the Esophagus and Digestive Tract Veneto Institute of Oncology IOV – IRCCS Padua Italy

Abstract

AbstractIntrabdominal 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.

Publisher

Wiley

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