Adaptive pathfinding by nucleokinesis during amoeboid migration

Motile cells encounter microenvironments with locally heterogeneous mechanochemical composition. Individual compositional parameters, such as chemokines and extracellular matrix pore sizes, are well known to provide guidance cues for pathfinding. However, motile cells face diverse cues at the same time, raising the question of how they respond to multiple and potentially competing signals on their paths. Here, we reveal that amoeboid cells require nuclear repositioning, termed nucleokinesis, for adaptive pathfinding in heterogeneous mechanochemical micro-environments. Using mammalian immune cells and the amoeba Dictyostelium discoideum, we discover that frequent, rapid and long-distance nucleokinesis is a basic component of amoeboid pathfinding, enabling cells to reorientate quickly between locally competing cues. Amoeboid nucleokinesis comprises a two-step polarity switch and is driven by myosin-II forces that readjust the nuclear to the cellular path. Impaired nucleokinesis distorts path adaptions and causes cellular arrest in the microenvironment. Our findings establish that nucleokinesis is required for amoeboid cell navigation. Given that many immune cells, amoebae, and some cancer cells utilize an amoeboid migration strategy, these results suggest that nucleokinesis underlies cellular navigation during unicellular biology, immunity, and disease. imageHow migrating cells prioritize chemical and mechanical guidance cues during their pathfinding in the local microenvironment is largely unknown. This study shows that amoeboid cell migration towards dominant chemotactic and mechanical pore size cues involves long-distance nuclear repositioning that is driven by actomyosin contractility.Immune cell migration towards dominant chemotactic guidance cues into narrow microenvironmental pores requires fast and long-distance intracellular repositioning of the nucleus (nucleokinesis) towards the cellular path.Nucleokinesis in amoeboid migrating cells requires a two-step polarity switch in the nucleus-MTOC axis configuration.Nucleokinesis during amoeboid migration is driven by myosin-II forces and is regulated by the RhoA guanine nucleotide exchange factor GEF-H1/Lfc.Major principles of amoeboid nucleokinesis are conserved between mammalian immune cells (dendritic cells, T cells) and the amoeba Dictyostelium discoideum. Integration of complex chemical and mechanical guidance cues by migrating immune cells and unicellular amoebae requires actomyosin-dependent nuclear repositioning.image