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.

Causes and consequences of nuclear envelope alterations in tumour progression

“…Cells can navigate these tight spaces by remodeling ECM fibers to modify their environment, including through ECM degradation by secreted matrix metalloproteases (MMPs), which are upregulated in many cancers and associated with poor prognosis (Coussens et al, 2002). Alternatively, cells can deform to squeeze through the available space (McGregor et al, 2016). This versatility may have contributed to the failure of MMP inhibitors to improve patient outcome in clinical trials (Coussens et al, 2002).…”

“…This versatility may have contributed to the failure of MMP inhibitors to improve patient outcome in clinical trials (Coussens et al, 2002). While the dynamic cytoplasm deforms easily to fit through micron-scale spaces, the nucleus is the largest and stiffest cellular organelle, and nuclear deformation can impose a rate-limiting step on migration in 3D environments (McGregor et al, 2016; Wolf et al, 2013). Accordingly, cells migrating in 3D collagen matrices show extensive nuclear deformation when MMP activity is inhibited, and sufficiently small pore sizes can lead to complete stalling of cell movement as the nucleus becomes ‘trapped’ in the dense network (Wolf et al, 2013).…”

Multiple mechanisms of 3D migration: the origins of plasticity

“…Interestingly, the relative constraints placed on the machinery for moving the nucleus by a particular 3D environment (Box 1) appears to correlate with the level of adhesion and actomyosin contractility required for overall cell migration (reviewed recently in [50]).…”

Recent advances in understanding nuclear size and shape

“…47 Nuclear volume also influences cell migration efficiency, 48 and expression of certain lamin mutants or altering lamin expression levels affect nuclear deformability and cell migration. [49][50][51][52] Knocking down lamin B1 in HeLa cells led to an increase in lamina meshwork size, formation of NE blebs enriched in lamin A/C, and increased nucleoplasmic lamin A mobility. 53 Reduced lamin B1 levels are frequently associated with altered nuclear and cell shape and increased cellular senescence.…”