Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations

Abstract

Cell polarization and directional cell migration can display random, persistent, and oscillatory dynamic patterns. However, it is not clear whether these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent, and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all of these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechanochemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions. cell polarization | cell migration | mechanochemical feedback | Rho-family small GTPases | extracellular matrix C ell migration involves complex interactions with the extracellular matrix (ECM) (1-4). Beyond providing cells with the substratum for adhesion and traction during the migration process, the ECM can activate signaling networks through biochemical engagement of the integrin complexes within focal adhesions (FAs) (5-7). The signaling pathways activated by integrins can impinge on the Rho-family small GTPases that are thought to be central regulators of cell polarity and migration (8-10). Varying ECM density can differentially control activation of two proteins belonging to this family, Rac1 and RhoA, which frequently display antagonistic interactions (11,12). Activation of Rac1 and RhoA can in turn regulate the mechanical properties of the cell, thus influencing how the cell interfaces with complex local organization of ECM fibers (13-15). The intricate nature of this ECM-Rac1-RhoA feedback interaction and the wide diversity of topographic ECM structures have made comprehensive analysis of the resulting cell migration behavior very challenging.In vivo cell migration can display diverse dynamic patterns. It can vary from random exploratory migration characterized by poor FA formation, frequent pseudopod extension, and a lack of stress fibers in dense 3D ECM (so-called 3D cell migration) to highly persistent migration along single ECM fibers in sparse 3D ECM (essentially 1D cell migration) (16-18). Recently, oscillatory migration patterns have also been observed following perturbation of cytoskeletal components, with cells retra...

A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns

“…Recent analysis suggested that these matrix re-arrangements can be well approximated in experiments, using matrix-mimicking nano-fabricated platforms that allow for controlled variation of the model matrix structure and chemical composition [9]. In particular, in our experimental analysis with melanoma cell lines we found that individual cells can display diverse polarity patterns when migrating in areas of the model matrix with various degrees of anisotropy [10]. Having this type of controlled micro-environment can allow one to develop mechanistic models [11] of cell polarity control and to test them by checking for consistency between model predictions and experimental results.…”

A Rho-GTPase based model explains spontaneous collective migration of neural crest cell clusters

“…Thus, the model offers an explanation for the origin of POP; it is an emergent behavior based on COA and CIL rather than a separate mechanism to be postulated in addition to these two. This hypothesis can be tested by experiments that use drugs to partially suppress various proteins (or their activation levels) in the Rho GTPase signaling pathway [58,59]. The resulting impairment of collective migration can be compared with model predictions of how COA, CIL and POP are affected by modulating the suitable Rac1 and RhoA rate constants.…”

Periodic propagating waves coordinate RhoGTPase network dynamics at the leading and trailing edges during cell migration

“…Rho GTPases are core regulators of mesenchymal and amoeboid cell migration. They integrate multiple internal and external cues (Campa et al, 2015;Devreotes et al, 2017;Lin et al, 2015;Park et al, 2017;Park et al, 2019) and relay information to a variety of cellular protein machineries, including proteins driving actin polymerization and cytoskeleton rearrangements, thereby enabling cell migration (Warner et al, 2019). Although molecular details of Rho GTPaseeffector interactions have been elaborated, we still lack an overall picture of how these GTPase activities and effector interactions are coordinated between the leading and trailing edge in order to enable cell movement.…”