CSIG-19. CANCER STEM CELL MEDIATED F11 DRIVES HYPER-THROMBOTIC ACTIVITY IN GLIOBLASTOMA

Abstract

Abstract Cancer-related thrombosis is the second leading cause of death for cancer patients and glioblastoma (GBM), the most common primary malignant brain tumor, is associated with approximately a 30% risk of venous thromboembolism, deep vein thrombosis, or pulmonary embolisms. While this remains a major clinical issue, the interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, including GBM. GBM is a tumor which contains a high degree of cellular heterogeneity and has populations of therapeutically resistant cancer stem cells (CSCs) that drive tumor growth. Histologically CSCs are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcome in many cancers and while platelets are known to promote progression of other tumors. Our previous work demonstrated that CSCs co-opt and activate platelets to promote CSC growth by intrinsically producing thrombin via a cell intrinsic functional coagulation cascade. These findings provided further evidence that CSCs readily execute a highly liver-specific gene expression program that is mechanistically linked to GBM growth. We now demonstrate thrombin and platelet expression in GBM patient specimen creates a hyper-thrombotic GBM tumor-microenvironment. Further, genetic targeting of the CSC intrinsic coagulation cascade, via knockdown of coagulation factor 11 (F11), reduces CSC growth and tumor formation while also decreasing the ability for CSCs to activate platelets, subsequently decreasing the hyper-thrombotic state seen in GBM. Our observations suggest that CSCs execute a cell intrinsic coagulation mechanism to contribute to the hyper-thrombotic tumor-microenvironment seen in GBM and may shed light onto mechanisms of cancer associated thrombosis in not only GBM, but also other malignancies.