Systemic coagulopathy drives host lethality in a new Drosophila tumor model

Abstract

Malignant tumors trigger a complex network of inflammatory and wound repair responses, prompting Dvoraks characterization of tumors as wounds that never heal 1. Some of these responses lead to profound defects in blood clotting, such as Disseminated Intravascular Coagulopathy (DIC), which correlate with poor prognoses 2-4. Here, we demonstrate that a new tumor model in Drosophila provokes phenotypes that recapitulate coagulopathies observed in patients. Fly ovarian tumors overproduce multiple secreted components of the clotting cascade and trigger hypercoagulation of fly blood (hemolymph). Hypercoagulation occurs shortly after tumor induction and is transient; it is followed by a hypocoagulative state that is defective in wound healing. Cellular clotting regulators accumulate on the tumor over time and are depleted from the body, suggesting that hypocoagulation is caused by malignant growth exhaustion of host clotting components. Interestingly, clinical studies have suggested that lethality in patients with high serum levels of clotting components can be independent of thrombotic events 5,6. We show that rescuing coagulopathy improves survival of tumor-bearing flies, despite the fact that flies have an open circulatory system. Our work establishes a platform for identifying alternative mechanisms by which tumor-driven coagulopathy triggers early mortality, as well as exploring other conserved mechanisms of host responses to chronic wounds.