During metazoan development, immune surveillance and cancer dissemination, cells migrate in complex three-dimensional microenvironments 1-3. These spaces are crowded by cells and extracellular matrix, generating mazes with differently sized gaps that are typically smaller than the diameter of the migrating cell 4,5. Most mesenchymal and epithelial cells and some, but not all, cancer cells actively generate their migratory path using pericellular tissue proteolysis 6. By contrast, amoeboid cells such as leukocytes use non-destructive strategies of locomotion 7 , raising Reprints and permissions information is available at http://www.nature.com/reprints.

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..

Cell migration is fundamental for the immune response, development, and morphogenesis. For navigation through complex and ever-changing environments, migrating cells require a balance between a stable leading-edge, which is necessary for directional migration, and some unstable features to enable the required dynamic behaviors. The leading edge is often composed of actin-driven protrusions including lamellipodia and ruffles with continuously changing membrane curvature. Whether their membrane topography affects the cell's leading edge and motion persistence in complex environments remains unknown. To study this, we combined a theoretical analysis with machine learning-based segmentation for time-resolved TIRF microscopy, membrane topography analysis from electron microscopy images and microfluidics. We discovered that cell motion persistence and directionality, in both freely moving and environmentally-constrained cells, strongly depend on the curvature-sensing protein Snx33. Specifically, Snx33 promotes leading edge instabilities by locally inhibiting WAVE2- driven actin polymerization in a curvature-dependent manner. Snx33 knockout cells migrate faster and are more persistent during unobstructed migration, but fail when a change in direction is required. Thus, Snx33 is key for steering cell motility in complex environments by facilitating contact inhibition of locomotion and promoting efficient turning. These results identify cell surface topography as an organizing principle at the cell periphery that directs cell migration.

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Immune responses crucially rely on the rapid and coordinated locomotion of leukocytes. While it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how such gradients are generated, maintained and modulated. Combining experiment and theory on leukocyte chemotaxis guided by the G protein-coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR-desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, thereby dynamically shaping the spatio-temporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, as well as provide a guidance cue for other co-migrating cells. Such dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization.

Reading, interpreting and crawling along gradients of chemotactic cues is one of the most complex questions in cell biology. In this issue, Georgantzoglou et al. (2022. J. Cell. Biol.https://doi.org/10.1083/jcb.202103207) use in vivo models to map the temporal sequence of how neutrophils respond to an acutely arising gradient of chemoattractant.