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

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.This work was partly developed at IPATIMUP, an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and I3S. This work was supported by FEDER–Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020–Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT–Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). This research was funded by projects PTDC/MEC-ONC/29503/ 2017 (to L.D.), NORTE 2020 grant numbers NORTE-01-0145-FEDER-000029, NORTE-01-0145-FEDER-000003, Wilhelm Sander Stiftung 2018.010.1 (to F.J.), Swiss Cancer League KLS-3841-02-2016 (to F.J.), and FCT PhD fellowship number SFRH/BD/111885/2015 (to R.C.) We would like to thank Dr. Ronny Drapkin (University of Pennsylvania) for sharing the fallopian tube cell lines