Eukaryotic cells migrate by coupling the intracellular force of the actin cytoskeleton to the environment. While force-coupling is usually mediated by transmembrane adhesion receptors, especially these of the integrin family, amoeboid cells like leukocytes can migrate extremely fast despite very low adhesive forces 1 . We show that leukocytes cannot only migrate under low adhesion but indeed can transduce forces in the complete absence of transmembrane force coupling. When confined within three-dimensional environments, they use the topographic features of the substrate to propel themselves. Here, the retrograde flow of the actin cytoskeleton follows the texture of the substrate, creating shear forces sufficient to drive deformations towards the back of the cell. Notably, adhesion dependent and adhesion independent migration are not exclusive but rather variants of the same principle of coupling retrograde actin flow to the environment and thus can potentially operate simultaneously. As adhesion free migration is independent of the chemical composition of the environment it renders cells completely autonomous in their locomotive behavior..

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Summary When crawling through the body, leukocytes often traverse tissues that are densely packed with extracellular matrix and other cells, and this raises the question: How do leukocytes overcome compressive mechanical loads? Here, we show that the actin cortex of leukocytes is mechanoresponsive and that this responsiveness requires neither force sensing via the nucleus nor adhesive interactions with a substrate. Upon global compression of the cell body as well as local indentation of the plasma membrane, Wiskott-Aldrich syndrome protein (WASp) assembles into dot-like structures, providing activation platforms for Arp2/3 nucleated actin patches. These patches locally push against the external load, which can be obstructing collagen fibers or other cells, and thereby create space to facilitate forward locomotion. We show in vitro and in vivo that this WASp function is rate limiting for ameboid leukocyte migration in dense but not in loose environments and is required for trafficking through diverse tissues such as skin and lymph nodes.

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