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

Abstract

Protrusion and retraction of lamellipodia are common features of eukaryotic cell motility. As a cell migrates through its extracellular matrix (ECM), lamellipod growth increases cell-ECM contact area and enhances engagement of integrin receptors, locally amplifying ECM input to internal signaling cascades. In contrast, contraction of lamellipodia results in reduced integrin engagement that dampens the level of ECM-induced signaling. These changes in cell shape are both influenced by, and feed back onto ECM signaling. Motivated by experimental observations on melanoma cells lines (1205Lu and SBcl2) migrating on fibronectin (FN) coated topographic substrates (anisotropic post-density arrays), we probe this interplay between intracellular and ECM signaling. Experimentally, cells exhibited one of three lamellipodial dynamics: persistently polarized, random, or oscillatory, with competing lamellipodia oscillating out of phase (Park et al., 2017). Pharmacological treatments, changes in FN density, and substrate topography all affected the fraction of cells exhibiting these behaviours. We use these observations as constraints to test a sequence of hypotheses for how intracellular (GTPase) and ECM signaling jointly regulate lamellipodial dynamics. The models encoding these hypotheses are predicated on mutually antagonistic Rac-Rho signaling, Rac-mediated protrusion (via activation of Arp2/3 actin nucleation) and Rho-mediated contraction (via ROCK phosphorylation of myosin light chain), which are coupled to ECM signaling that is modulated by protrusion/contraction. By testing each model against experimental observations, we identify how the signaling layers interact to generate the diverse range of cell behaviors, and how various molecular perturbations and changes in ECM signaling modulate the fraction of cells exhibiting each. We identify several factors that play distinct but critical roles in generating the observed dynamic: (1) competition between lamellipodia for shared pools of Rac and Rho, (2) activation of RhoA by ECM signaling, and (3) feedback from lamellipodial growth or contraction to cell-ECM contact area and therefore to the ECM signaling level.

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.…”

Computational modeling of single‐cell mechanics and cytoskeletal mechanobiology

“…While it is known that ECM signaling initiates a number of signaling cascades that regulate acto‐myosin reorganization, downstream growth or contraction of lamellipodia (which involve actin and myosin dynamics) influences the level of physical cell contact with the substrate and thus levels of ECM signaling. These feedbacks in turn influence the persistence of migration, which can be manipulated by augmenting the topography of the substrate or the density of fibronectin coating.…”

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

“…A canonic description of mesenchymal cell migration portrays mutually separated zones of Rac1-GTP and RhoA-GTP in polarized cells where Rac1-GTP dominates at the leading edge and RhoA-GTP dominates at the contracted cell rear (Holmes and Edelstein-Keshet, 2016;Holmes et al, 2017;Kunida et al, 2012;Kurokawa and Matsuda, 2005;Pertz et al, 2006;Wang et al, 2013;Zmurchok and Holmes, 2020). This distinct distribution of RhoA and Rac1 activities along polarized cells is explained by a mutual antagonism of RhoA and Rac1 (Edelstein-Keshet et al, 2013;Mori et al, 2008) mediated by their downstream effectors (Byrne et al, 2016;Guilluy et al, 2011;Pertz, 2010).…”