OC 12.5 - Canonical and Non-Canonical FXII Functions Synergistically Drive Ovarian Cancer-Associated Thrombosis and Tumor Progression

Background: High-grade serous epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer and has a high incidence of venous thromboembolism (VTE). Our lab has previously demonstrated that FXII contributes to deep vein thrombosis (DVT) through distinct zymogen and enzymatic (FXIIa) functions. Neutrophil-derived FXII operates upstream of systemic FXII as an autocrine messenger through its receptor urokinase plasminogen activator receptor (uPAR), to promote neutrophil trafficking at sites of inflammation and venous stasis. At these sites, neutrophils drive tissue inflammation and lead to amplification of thrombin formation, in part mediated by neutrophil extracellular traps (NETs) and FXII contact activation.

Aims: To elucidate the role of FXII in ovarian cancer-associated thrombosis and tumor biology.

Methods: We utilized a murine model of EOC and IVC ligation studies in wild-type (WT), FXII-deficient (F12-/-), and uPAR-deficient (Plaur-/-) mice to assess the therapeutic potential of targeting FXII activities on thrombotic potential and tumor behavior.

Results: FXII deficiency restricted baseline plasma thrombin-antithrombin (TAT) levels in tumor-bearing F12-/- (F12-/- -T) mice compared to tumor-bearing WT-T animals (Figure 1A), indicating that canonical FXII activation contributes to the hypercoagulable state of ovarian cancer. Importantly, F12-/- and Plaur-/- mice failed to develop extensive tumor dissemination and ascites compared to WT littermates (Figure 1B-D). In vivo, EOC tumors grown in F12-/- hosts exhibited reduced expression of pro-mesenchymal markers consistent with reduced epithelial-to-mesenchymal transition (EMT). Mechanistically, WT neutrophils, but not F12-/- neutrophils, augmented tumor cell EMT. Finally, tumor-bearing WT mice treated with inhibitors that target the FXII-uPAR interaction without compromising FXIIa activity, had significantly reduced thrombus sizes compared to vehicle-treated WT controls.

Conclusion(s): These results support that zymogen FXII and FXIIa synergistically drive ovarian cancer thrombosis and tumor progression, suggesting that targeting FXII functions has the potential to improve prothrombotic risk and perturb tumor-host interactions to suppress tumorigenesis and metastasis.