Nuclear mechanics during cell migration

Abstract

During cell migration, the movement of the nucleus must be coordinated with the cytoskeletal dynamics at the leading edge and trailing end, and, as a result, undergoes complex changes in position and shape, which in turn affects cell polarity, shape, and migration efficiency. We here describe the steps of nuclear positioning and deformation during cell polarization and migration, focusing on migration through three-dimensional matrices. We discuss molecular components that govern nuclear shape and stiffness, and review how nuclear dynamics are connected to and controlled by the actin, tubulin and intermediate cytoskeleton-based migration machinery and how this regulation is altered in pathological conditions. Understanding the regulation of nuclear biomechanics has important implications for cell migration during tissue regeneration, immune defence and cancer.

Figure 1

Nuclear diversity and deformation in cancer cells. (A) Tip of an invasion zone of a primary human melanoma, showing heterogeneously shaped, elongated and partly deformed nuclei. Arrowheads in details, local deformation. (B) Central region of an invasion zone in human fibrosarcoma exhibiting elongated and partly deformed cigar-shaped nuclei of variable size. (C) Effect of altered nuclear envelope composition on mammary epithelial cells. Genetically modified MCF10A breast epithelial cells that stably express lamin B receptor (LBR↑), lamin A (Lamin A↑) or shRNA directed against lamins A and C (Lamin A/C ↓) or control vector (mock). Cells overexpressing LBR or having reduced expression of lamins A/C show striking similarities to the nuclear shape observed in many cancer cells. Both modifications result in decreased nuclear stiffness (J Lammerding, unpublished). Overexpression of lamin A results in rounder (and stiffer) nuclei. Bars, 10μm.

Figure 2

Nuclear dynamics and deformation during cell migration. (A) HT-1080 cells expressing DsRed2 in the cytoplasm and H2B/eGFP in the nucleus migrating in 3D collagen lattice. Confocal time-lapse sequence in mid-density (3.3 mg/ml) collagen shows phases of shape change. Bar, 10 μm. (B) Initial cell polarization leads to rotational dynamics (I) followed by initial translocation of the nucleus (II). When physical barriers are encountered, the nucleus deforms during forward sliding (III). In the absence of ECM degradation capability, the nuclear deformation is more pronounced (IIIa). Alternatively, the cell degrades ECM structures proteolysically (green color) and generates a small trail-like matrix defect (IIIb, asterisk), thereby minimizing nuclear deformation.

Figure 3

Structural proteins involved in nuclear morphology, stability and interaction with the cytoskeleton. Top panel: Cell migrating through 3D matrix of extracellular matrix fibers (brown) and encountering a narrow constriction (not drawn to scale). Orange dots denote focal contacts; pink lines microtubules, green lines intermediate filaments, and blue structures actin filaments. (Inset). The lower panel shows molecules contributing to nuclear stiffness and nuclear-cytoskeletal coupling. Lamins underly the inner nuclear membrane and also form stable structures within the nuclear interior. Membrane proteins such as emerin, LBR, and SUN1/2 are retained at the inner nuclear membrane through their interactions with lamins, chromatin, or other nuclear proteins. Nesprins bind to SUN proteins across the perinuclear space and can directly interact with actin filaments (nesprins-1 and -2) or with intermediate filaments via plectin (nesprin-3). Nesprins-1 and -2 have been proposed to bind to microtubules via kinesin or dynein.