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.

Neutrophil extracellular trap formation correlates with improved overall survival in ovarian cancer

“…This approach supports the analysis of pathomechanisms and related adaptative responses such as inflammation in great detail [7,8]. With regard to high grade serous ovarian cancer (HGSOC), it allowed us to identify predictive marker profiles [9] as well as novel drug targets [10]. A distinct role of the immune system in ovarian cancer affecting the kind of tumor spread of ovarian cancer was described by us already previously [11].…”

Neutrophil Extracellular Trap Formation Correlates with Favorable Overall Survival in High Grade Ovarian Cancer

“…This approach supports the analysis of pathomechanisms and related adaptative responses such as inflammation in great detail [7,8]. With regard to high grade serous ovarian cancer (HGSOC), it allowed us to identify predictive marker profiles [9] as well as novel drug targets [10]. A distinct role of the immune system affecting the kind of tumor spread of ovarian cancer was described by us already previously [11].…”

Multi-platform Affinity Proteomics Identify Proteins Linked to Metastasis and Immune Suppression in Ovarian Cancer Plasma

“…Several of these proteins have been described in the literature as mediators of ovarian cancer progression, including associations of their expression in tumor tissue or blood or ascites levels with ovarian cancer survival, for instance IL-6, GDF15, OPN/SST1, PVRL4, and VEGFA (13, 28, 36–43). One of the proteins with the most significant difference in Figure 1, i.e., SPINT2, however, has not been linked to HGSC prior to the present study and is discussed in more detail in the subsequent section.…”