Anisotropic forces from spatially constrained focal adhesions mediate contact guidance directed cell migration

Arja Ray,Deok-Ho Kim,Rachel M Edwards,Paolo P Provenzano,Zaw Win,Patrick W Alford,Oscar Lee

doi:10.1038/ncomms14923

Abstract

Directed migration by contact guidance is a poorly understood yet vital phenomenon, particularly for carcinoma cell invasion on aligned collagen fibres. We demonstrate that for single cells, aligned architectures providing contact guidance cues induce constrained focal adhesion maturation and associated F-actin alignment, consequently orchestrating anisotropic traction stresses that drive cell orientation and directional migration. Consistent with this understanding, relaxing spatial constraints to adhesion maturation either through reduction in substrate alignment density or reduction in adhesion size diminishes the contact guidance response. While such interactions allow single mesenchymal-like cells to spontaneously ‘sense’ and follow topographic alignment, intercellular interactions within epithelial clusters temper anisotropic cell–substratum forces, resulting in substantially lower directional response. Overall, these results point to the control of contact guidance by a balance of cell–substratum and cell–cell interactions, modulated by cell phenotype-specific cytoskeletal arrangements. Thus, our findings elucidate how phenotypically diverse cells perceive ECM alignment at the molecular level.

Highlights

Directed migration by contact guidance is a poorly understood yet vital phenomenon, for carcinoma cell invasion on aligned collagen fibres
Several reports exist in the literature alluding to the fact that cells respond to extracellular matrix (ECM) alignment, a close examination suggested to us that the degree to which different cell types respond to topographic alignment may vary[23,24,25]
Analysis of combined multiphoton excitation (MPE) and second harmonic generation (SHG) imaging data of carcinoma cells interacting with aligned collagen at the tumour–stroma boundary reveals phenotypically distinct cancer cells ranging from clustered, classically epithelial to single, mesenchymal-like cells associated with the anisotropic ECM (Fig. 1a)

Summary

Introduction

Directed migration by contact guidance is a poorly understood yet vital phenomenon, for carcinoma cell invasion on aligned collagen fibres. We demonstrate that for single cells, aligned architectures providing contact guidance cues induce constrained focal adhesion maturation and associated F-actin alignment, orchestrating anisotropic traction stresses that drive cell orientation and directional migration. Consistent with this understanding, relaxing spatial constraints to adhesion maturation either through reduction in substrate alignment density or reduction in adhesion size diminishes the contact guidance response. While such interactions allow single mesenchymal-like cells to spontaneously ‘sense’ and follow topographic alignment, intercellular interactions within epithelial clusters temper anisotropic cell–substratum forces, resulting in substantially lower directional response. Our findings mechanistically explicate the observed diversity in responses to contact guidance across cell types and provide a biophysical perspective to understand and disrupt the directional guidance of carcinoma cells invading on aligned collagen fibres

Methods

Results

Conclusion