NECTIN4 (PVRL4) as Putative Therapeutic Target for a Specific Subtype of High Grade Serous Ovarian Cancer—An Integrative Multi-Omics Approach

Abstract

In high grade serous ovarian cancer patients with peritoneal involvement and unfavorable outcome would benefit from targeted therapies. The aim of this study was to find a druggable target against peritoneal metastasis. We constructed a planar—scale free small world—co-association gene expression network and searched for clusters with hub-genes associated to peritoneal spread. Protein expression and impact was validated via immunohistochemistry and correlations of deregulated pathways with comprehensive omics data were used for biological interpretation. A cluster up-regulated in miliary tumors with NECTIN4 as hub-gene was identified and impact on survival validated. High Nectin 4 protein expression was associated with unfavorable survival and (i) reduced expression of HLA genes (mainly MHC I); (ii) with reduced expression of genes from chromosome 22q11/12; (iii) higher BCAM in ascites and in a high-scoring expression cluster; (iv) higher Kallikrein gene and protein expressions; and (v) substantial immunologic differences; locally and systemically; e.g., reduced CD14 positive cells and reduction of different natural killer cell populations. Each three cell lines with high (miliary) or low NECTIN4 expression (non-miliary) were identified. An anti-Nectin 4 antibody with a linked antineoplastic drug−already under clinical investigation−could be a candidate for a targeted therapy in patients with extensive peritoneal involvement.

Keywords

• Nectin 4
• NECTIN4
• PVRL4
• tumor spread
• miliary or non-miliary
• fallopian tube secretory epithelial cells (FTE)
• ovarian surface epithelial cells (OSE)