OC 66.1 - The Factor XII-uPAR Axis Drives Ovarian Cancer Maintenance and Progression

Background: Epithelial ovarian cancer (EOC) is the leading cause of cancer death in women. Most commonly, EOC forms loosely attached outgrowths that transit through the peritoneal fluid and attach to new sites. This unusual route of dissemination is associated with tumor heterogeneity, development of resistant disease, and abdominal organ obstruction. The urokinase receptor uPAR has long been recognized to assist the directional movement of migrating cells and elicits a plethora of cellular responses, several of which are mediated through its association with coagulation Factor XII (FXII).

Aims: Because FXII and uPAR can be produced by both ovarian tumor cells and the host, we investigated if the FXII-uPAR axis synergistically influences tumor biology.

Methods: We accessed publicly available single-cell RNA-seq data from human ovarian tumors, performed ex vivo silencing studies, and used in vivo murine models of EOC.

Results: Single-cell RNAseq data showed that FXII is robustly expressed in EOC tumor cells themselves, whereas uPAR is enriched in tumor stromal cells (Fig 1A). Based on these findings, we next investigated if absence of host FXII and uPAR is sufficient at reducing tumor growth & dissemination. In murine studies, ID8 EOC cells resulted in significantly higher tumor burden in WT mice compared to F12-/- and Plaur-/- mice (Fig 1B). Invariably, loss of host FXII or uPAR resulted in tumors with significantly reduced vascularity, increased apoptotic rates and reduced epithelial-to-mesenchymal transition (EMT, Fig 1C-G). However, FXII deficiency was uniquely associated with increased expression of epithelial E-cadherin, indicative of reduced tumor invasive potential. These findings were recapitulated after silencing of F12 expression with an siRNA strategy (Fig 1C-G).

Conclusion(s): These data show that FXII-uPAR are differentially expressed in the ovarian tumor microenvironment where they support tumor maintenance and progression. Targeting this interaction may prove to be an effective therapeutic strategy for persistent or recurrent EOC.