Squish and squeeze-the nucleus as a physical barrier during migration in confined environments

Abstract

From embryonic development to cancer metastasis, cell migration plays a central role in health and disease. It is increasingly becoming apparent that cells migrating in three-dimensional (3-D) environments exhibit some striking differences compared with their well-established 2-D counterparts. One key finding is the significant role the nucleus plays during 3-D migration: when cells move in confined spaces, the cell body and nucleus must deform to squeeze through available spaces, and the deformability of the large and relatively rigid nucleus can become rate-limiting. In this review, we highlight recent findings regarding the role of nuclear mechanics in 3-D migration, including factors that govern nuclear deformability, and emerging mechanisms by which cells apply cytoskeletal forces to the nucleus to facilitate nuclear translocation. Intriguingly, the 'physical barrier' imposed by the nucleus also impacts cytoplasmic dynamics that affect cell migration and signaling, and changes in nuclear structure resulting from the mechanical forces acting on the nucleus during 3-D migration could further alter cellular function. These findings have broad relevance to the migration of both normal and cancerous cells inside living tissues, and motivate further research into the molecular details by which cells move their nuclei, as well as the consequences of the mechanical stress on the nucleus.

Figure 1. Schematic overview of the physical connections between the nucleus and cytoskeleton, and their roles in moving the nucleus through confined spaces

(A) At the nuclear periphery, chromatin interacts with lamins at lamina-associated domains (LADs). SUN domain proteins (SUN1 and SUN2) are anchored to the nuclear lamina and other components of the nuclear interior by their C-terminus. The N-terminal luminal long stalks and SUN domains of SUN1/2 form trimers that interact with KASH domain proteins located in the outer nuclear membrane (nesprin-1/-2/-3, along with the cell-type specific nesprin-4 and KASH5), forming the LINC complex [101]. The strong interaction between SUN domain trimers and the KASH domains provide the basis to mechanically couple the nuclear interior with the cytoskeleton—nesprins interact directly with actomyosin bundles, or indirectly with microtubules and intermediate filaments via intermediary proteins (such as kinesin, dynein, plectin) [55]. Mechanical force transmission via nucleo-cytoskeletal coupling may also trigger mechanotransduction events, ranging from the recruitment of lamins to the LINC complex to changes in chromatin organization and gene expression, which may further impact cell migration processes. (B) Cytoskeletal organization and dynamics during migration in confined 3-D environments. As the cell passes through narrow pores, the nucleus separates the cell into front and back ends. The insets depict proposed mechanisms by which the cytoskeleton translocates the nucleus through confined spaces, including pushing via actomyosin contraction at the posterior of the nucleus (1), pulling via actomyosin contraction facilitated by intermediate filaments (2), pulling via microtubule-associated motors (3), and rotation via microtubule-associated motors (4).