Ratchetaxisin channels: cells move directionally by pushing walls asymmetrically

Abstract

Cell motility is essential in a variety of biological phenomena ranging from early development to organ homeostasis and diseases. This phenomenon was so far mainly studied and characterized on flat surfaces in vitro whereas this situation is rarely seen in vivo. Recently, cell motion in 3D microfabricated channels was reported to be possible, and it was shown that confined cells push on walls. However, rules setting cell directions in this context were not characterized yet. Here, we show by using assays that ratchetaxis operates in 3D ratchets on fibroblasts and on epithelial cancerous cells. Open ratchets rectify cell motion, whereas closed ratchets impose a direct cell migration along channels set by the cell orientation at the channel entry point. We also show that nuclei are pressed at constrictions zones through mechanisms involving dynamic asymmetries of focal contacts, stress fibers, and intermediate filaments. Interestingly, cells do not pass these constricting zones when defective in the keratin fusion implicated in squamous cancer. By combining ratchetaxis with chemical gradients, we finally report that cells are sensitive to local asymmetries in confinement and that topological and chemical cues may be encoded differently by cells. Altogether our ratchet channels could mimic small blood vessels where cells are confined: cells would probe local asymmetries which would determine their entry into tissues and direction. Our results could shed light on invasions mechanisms in cancer.

All Roads Lead to Directional Cell Migration

“…The signalling networks of PI3K and ROCK that control topotaxis, in which direction of migration is mediated by gradients of topographic features, are known to regulate cell migration via Rho GTPases and therefore it is proposed that topotaxis likely works by similar downstream canonical mechanisms of small GTPases and actin regulation [116]. Directional migration by means of spatially determined adhesion sites may be related to the organisation of stress fibers that allows them to organise their forces to pass through an asymmetric topology [117].…”

“…Additionally, a chemical gradient in the opposite direction to the ratchet can drive the cells to move 'against' the favourable direction of motion as set up by the ratchet of adhesive sites, whereas when the chemotactic gradient is removed, the cells fail to continue moving in this direction [117]. Likewise, topotactic and chemotactic cues have additive effects on the directional migration of Dictyostelium [122].…”

Rectification of confined soft vesicles containing active particles

“…It is quite remarkable that this model, which could be considered as what is possibly the simplest active model of a cell, can generate a sufficient level of complexity to produce behavior, such as ratchetaxis of a living cell when placed in asymmetric confining channels. 24…”

“…Yet this is an important problem especially given the experimental demonstration of directional motion of fibroblasts and epithelial cancerous cells when confined within asymmetric periodic channels. 24 While cells are complicated entities involving sub-structures such as the cytoskeleton, here, we show that rectification can be achieved by far simpler deformable entities such as a two dimensional soft vesicle that encloses spherical active particles.…”