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Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis

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Abstract

During epithelial ovarian cancer (EOC) progression, intraperitoneally disseminating tumor cells and multicellular aggregates (MCAs) present in ascites fluid adhere to the peritoneum and induce retraction of the peritoneal mesothelial monolayer prior to invasion of the collagen-rich submesothelial matrix and proliferation into macro-metastases. Clinical studies have shown heterogeneity among EOC metastatic units with respect to cadherin expression profiles and invasive behavior; however, the impact of distinct cadherin profiles on peritoneal anchoring of metastatic lesions remains poorly understood. In the current study, we demonstrate that metastasis-associated behaviors of ovarian cancer cells and MCAs are influenced by cellular cadherin composition. Our results show that mesenchymal N-cadherin-expressing (Ncad+) cells and MCAs invade much more efficiently than E-cadherin-expressing (Ecad+) cells. Ncad+ MCAs exhibit rapid lateral dispersal prior to penetration of three-dimensional collagen matrices. When seeded as individual cells, lateral migration and cell–cell junction formation precede matrix invasion. Neutralizing the Ncad extracellular domain with the monoclonal antibody GC-4 suppresses lateral dispersal and cell penetration of collagen gels. In contrast, use of a broad-spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) to block endogenous membrane type 1 matrix metalloproteinase (MT1-MMP) activity does not fully inhibit cell invasion. Using intact tissue explants, Ncad+ MCAs were also shown to efficiently rupture peritoneal mesothelial cells, exposing the submesothelial collagen matrix. Acquisition of Ncad by Ecad+ cells increased mesothelial clearance activity but was not sufficient to induce matrix invasion. Furthermore, co-culture of Ncad+ with Ecad+ cells did not promote a ‘leader–follower’ mode of collective cell invasion, demonstrating that matrix remodeling and creation of invasive micro-tracks are not sufficient for cell penetration of collagen matrices in the absence of Ncad. Collectively, our data emphasize the role of Ncad in intraperitoneal seeding of EOC and provide the rationale for future studies targeting Ncad in preclinical models of EOC metastasis.

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Acknowledgements

This work was supported in part by Research Grants RO1CA109545 and RO1CA086984 (both to MSS) from the National Institutes of Health/National Cancer Institute, the Leo and Anne Albert Charitable Trust (to MSS); the Research Like a Champion grant (to YK and RL); the Walther Cancer Foundation Seeding Research in Cancer grant (to OK); NSF DGE1313583 (to EL); U01-HL116330 (to OK and MA) and University of Notre Dame Integrated Imaging Facility. We thank Dr Charles Tessier, Indiana University School of Medicine–South Bend for assistance with second-harmonic-generation imaging microscopy.

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  1. Y Klymenko and O Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA

    Y Klymenko

  2. Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA

    Y Klymenko, O Kim, E Loughran, J Yang, R Lombard, M Alber & M S Stack

  3. Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA

    O Kim & M Alber

  4. Department of Mathematics, University of California, Riverside, CA, USA

    O Kim & M Alber

  5. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    E Loughran, J Yang & M S Stack

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  1. Y Klymenko
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Klymenko, Y., Kim, O., Loughran, E. et al. Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis. Oncogene 36, 5840–5851 (2017). https://doi.org/10.1038/onc.2017.171

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