Abstract
Directional cell migration in dense three-dimensional (3D) environments critically depends upon shape adaptation and is impeded depending on the size and rigidity of the nucleus. Accordingly, the nucleus is primarily understood as a physical obstacle; however, its pro-migratory functions by stepwise deformation and reshaping remain unclear. Using atomic force spectroscopy, time-lapse fluorescence microscopy and shape change analysis tools, we determined the nuclear size, deformability, morphology and shape change of HT1080 fibrosarcoma cells expressing the Fucci cell cycle indicator or being pre-treated with chromatin-decondensating agent TSA. We show oscillating peak accelerations during migration through 3D collagen matrices and microdevices that occur during shape reversion of deformed nuclei (recoil), and increase with confinement. During G1 cell-cycle phase, nucleus stiffness was increased and yielded further increased speed fluctuations together with sustained cell migration rates in confinement when compared to interphase populations or to periods of intrinsic nuclear softening in the S/G2 cell-cycle phase. Likewise, nuclear softening by pharmacological chromatin decondensation or after lamin A/C depletion reduced peak oscillations in confinement. In conclusion, deformation and recoil of the stiff nucleus contributes to saltatory locomotion in dense tissues.This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.
Highlights
Cell migration is an essential process during development, tissue maintenance and immune function, but is of importance during pathological cell invasion, including cancer metastasis [1]
Respective nuclear shape changes (DNII, fluctuation) during phase IV peaks were two- to fivefold higher in confinement when compared with remaining events and to phase IV peaks in cells migrating in collagen in the presence of proteolysis
Congruent to lowered elasticity after chromatin decondensation, nuclei deformed more slowly during migration and their ability to change shape reduced by up to 60% compared to an untreated control
Summary
Cell migration is an essential process during development, tissue maintenance and immune function, but is of importance during pathological cell invasion, including cancer metastasis [1]. We have proposed a multi-step translocation cycle of the nucleus during confined three-dimensional (3D) cell migration consisting of (I) pressure application by the external constraint onto the nuclear membrane in the direction of migration, (II) beginning deformation of the nucleus by the formation of a local prolapse slowing down migration, (III) gliding of the compressed and deformed nucleus through the pore and (IV) rear release connected to rapid forward pushing and rounding (recoil) of the nucleus [13] Implicit to this cyclic process, the migration delay during phase II is consistent with the ‘physical barrier’ function of the nucleus and might represent a phase of storage of deformation energy, which is released as propulsive energy during phase IV, leading to short phases of increased migration. Our results indicate that deformation of the elastic nucleus during the passage of a constriction generates a recoil event that transforms into nuclear reshaping by rounding and, simultaneously, boosts nuclear propulsion and instantaneous migration velocity
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