Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell–induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapie

Dynamic Locomotion Gaits of a Compliantly Actuated Quadruped With SLIP-Like Articulated Legs Embodied in the Mechanical Design

The spring loaded inverted pendulum (SLIP) model has been extensively shown to be fundamental for legged locomotion. However, the way this low-order template model dynamics is anchored in high-dimensional articulated multibody systems describing compliantly actuated robots (and animals) is not obvious and has not been shown so far. In this letter, an articulated leg mechanism and a corresponding quadrupedal robot design are introduced, for which the natural oscillation dynamics is structurally equivalent to the SLIP. On the basis of this property, computationally simple and robust control methods are proposed, which implement the gaits of pronking, trotting, and dynamic walking in the real robotic system. Experiments with a compliantly actuated quadruped featuring only low-performance electrical drives validate the effectiveness of the proposed approach