Regulation of invasion and peritoneal dissemination of ovarian cancer by mesothelin manipulation

Ricardo Coelho,Nuno Mendes,Leonor David,Raquel Almeida,Verónica Ferreira,José Pedro Neves,Carla Bartosch,Francis Jacob,José Manuel Lopes,Mariana Nunes,Viola Heinzelmann-Schwarz,Ana Luísa Amaral,Raquel Portugal,Sara Ricardo,Yen-Lin Huang,Mónica Nuñez López

doi:10.1038/s41389-020-00246-2

Abstract

Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient’s outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLNhigh ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC.

Highlights

Peritoneal dissemination is a particular form of metastasis in ovarian[1], pancreatic[2] and gastrointestinal cancers[3]
Since high-grade serous carcinomas (HGSC), is the most frequent and aggressive histological subtype of EOC25,26 and is frequently associated with peritoneal carcinomatosis, we studied MSLN protein expression in three independent series
Immunocytochemistry evaluation of 64 cases of HGSC showed that 70.3% of the cases had MSLN overexpression (Allred score 7 and 8) (Fig. S1D)

Summary

Introduction

Peritoneal dissemination is a particular form of metastasis in ovarian[1], pancreatic[2] and gastrointestinal cancers[3]. In this multistep process of cancer dissemination, cancer cells detach from primary tumor, survive and circulate in the peritoneal fluid and implant through the mesothelial layer with subsequent peritoneal carcinomatosis[4,5]. The physiological function of MSLN, as well as its role in cancer, are still unclear, it was originally suggested that MSLN could have a role in cell adhesion[8]. The role in the adhesion process was further supported by evidence showing that binding of MSLN to mucin MUC16 could be important for the peritoneal

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Conclusion