Plasticity of cell migration: a multiscale tuning model

Abstract

Cell migration underlies tissue formation, maintenance, and regeneration as well as pathological conditions such as cancer invasion. Structural and molecular determinants of both tissue environment and cell behavior define whether cells migrate individually (through amoeboid or mesenchymal modes) or collectively. Using a multiparameter tuning model, we describe how dimension, density, stiffness, and orientation of the extracellular matrix together with cell determinants-including cell-cell and cell-matrix adhesion, cytoskeletal polarity and stiffness, and pericellular proteolysis-interdependently control migration mode and efficiency. Motile cells integrate variable inputs to adjust interactions among themselves and with the matrix to dictate the migration mode. The tuning model provides a matrix of parameters that control cell movement as an adaptive and interconvertible process with relevance to different physiological and pathological contexts.

Figure 1.

Cell morphologies, migration modes, and transitions. The nomenclature of interstitial migration modes is based on typical cell morphology (rounded or spindle-shaped) and pattern (individual, loosely connected, or collective). Each migration mode is governed by a set of molecular mechanisms (see details in Table I and Fig. 2), the regulation of which can change the style of migration. Most widely studied examples for alterations of migration mode are the mesenchymal-to-amoeboid transition or the collective-to-individual transition. The thick gray arrows indicate the direction of migration.

Figure 2.

The tuning model of cell migration. An integrated multiscale model to combine multiple interdependent parameters that impact migration mode. Each parameter is experimentally testable individually; however, in most cases they are interconnected with others (see text for details). Approximated parameter profiles of selected migration modes are indicated (colored lines). Modulation by increasing or decreasing the magnitude of any parameter may impact the resulting migration mode as well as the input strength of coregulated parameters. The format of the tuning model mimics the popular display of a graphic equalizer, which is integral to modern media display programs (e.g., Windows Media Player or QuickTime); the graphic interface serves to adjust the intensity of different wavelengths of the phono output independently to modify the sound profile.