Adaptive pathfinding by nucleokinesis during amoeboid migration

Abstract

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.

Principles of organelle positioning in motile and non-motile cells

“…For instance, fast-moving amoeboid cells, such as mammalian T cells, dendritic cells, and single-cell amoeba, position their nucleus directly behind the protrusive front (Renkawitz et al, 2019 ; Ishikawa-Ankerhold et al, 2022 ). This forward positioning of the nucleus is mediated by actomyosin contractility (Kroll et al, 2023 ) and is best described in relation to the centrosome, which typically localises to the cell centre of motile cells and behind the nucleus of fast-moving amoeboid cells (Fig. 1 ).…”

“…2D ). Indeed, long-distance repositioning events of the nucleus from ‘losing’ into ‘winning’ protrusions occur during the migration of dendritic cells, T cells, and the amoebae Dictyostelium discoideum (Kroll et al, 2023 ). This long-distance repositioning of the nucleus is efficiently mediated by actomyosin contractility, providing migrating cells the flexibility to efficiently adjust their path and intracellular content towards an emerging guidance cue, such as when chemotactic cues overrule mechanical pore size cues (Kroll et al, 2023 ).…”

“…Indeed, long-distance repositioning events of the nucleus from ‘losing’ into ‘winning’ protrusions occur during the migration of dendritic cells, T cells, and the amoebae Dictyostelium discoideum (Kroll et al, 2023 ). This long-distance repositioning of the nucleus is efficiently mediated by actomyosin contractility, providing migrating cells the flexibility to efficiently adjust their path and intracellular content towards an emerging guidance cue, such as when chemotactic cues overrule mechanical pore size cues (Kroll et al, 2023 ). While many immune cells like T cells and dendritic cells migrate with an amoeboid mode that is characterised by fast velocities, low-adhesiveness to the substrate, and dynamic cell shape changes, other immune cells like macrophages (Paterson and Lämmermann, 2021 ) and mast cells (Kaltenbach et al, 2023 ) employ a more mesenchymal migration mode that is slower and characterised by stronger adhesions to the substrate (Kameritsch and Renkawitz, 2020 ).…”

“…2B ), preventing the slowdown of motility (Renkawitz et al, 2019 ) and potentially reducing nuclear damage caused by extreme nuclear squeezing through pores (Denais et al, 2016 ; Raab et al, 2016 ). While these different functions of the nucleus during cell motility have been studied individually, they likely work in conjunction: when migrating cells encounter multiple ECM pores in front of them along their trafficking paths, the nucleus can act as a mechanical gauge for the different pores to choose the path of least resistance; but cells can also decide for narrow pores along strong chemotactic signals that can override the dismissive mechanical pore size cue (Kroll et al, 2023 ), which may be facilitated by the opening of the pore by nuclear wedging or proteolytic digestions.…”

“…Hence, the relative positioning of the centrosome is important for its function as a local protease secretion site and for the function of the nucleus as a mechanical gauge. Notably, while the positioning of the nucleus can dynamically change within a cell (see below), the centrosome typically maintains its position at the cell centre, as shown in motile fibroblasts (Gomes et al, 2005 ), Dictyostelium amoebae (Ishikawa-Ankerhold et al, 2022 ), and immune cells (Kroll et al, 2023 ). Notably, also the coordination of retraction appears to be mediated by organelle positioning: once the centrosome enters the winning protrusion of migrating dendritic cells, the remaining protrusions start to retract (Fig.…”