Systemic coagulopathy promotes host lethality in a new Drosophila tumor model.

Malignant tumors trigger a complex network of inflammatory and wound repair responses, prompting Dvorak's 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.2,3,4 Here, we demonstrate that a new tumor model in Drosophila provokes phenotypes that resemble 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 exhaustion of host clotting components. We show that rescuing coagulopathy by depleting a tumor-produced clotting factor improves survival of tumor-bearing flies, despite the fact that flies have an open (non-vascular) circulatory system. As clinical studies suggest that lethality in patients with high serum levels of clotting components can be independent of thrombotic events,5,6 our work establishes a platform for identifying alternative mechanisms by which tumor-driven coagulopathy triggers early mortality. Moreover, it opens up exploration of other conserved mechanisms of host responses to chronic wounds.

The (dys)functional extracellular matrix.

The extracellular matrix (ECM) is a major component of the biomechanical environment with which cells interact, and it plays important roles in both normal development and disease progression. Mechanical and biochemical factors alter the biomechanical properties of tissues by driving cellular remodeling of the ECM. This review provides an overview of the structural, compositional, and mechanical properties of the ECM that instruct cell behaviors. Case studies are reviewed that highlight mechanotransduction in the context of two distinct tissues: tendons and the heart. Although these two tissues demonstrate differences in relative cell-ECM composition and mechanical environment, they share similar mechanisms underlying ECM dysfunction and cell mechanotransduction. Together, these topics provide a framework for a fundamental understanding of the ECM and how it may vary across normal and diseased tissues in response to mechanical and biochemical cues. This article is part of a Special Issue entitled: Mechanobiology.