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.
Bibliographical noteFunding Information:
P.P.P. and this work was supported by a Research Scholar Grant, RSG-14-171-01-CSM from the American Cancer Society. This work was also supported by the NIH (R01CA181385 to P.P.P.; U54CA210190 University of Minnesota Physical Sciences in Oncology Center to P.W.A. and P.P.P.); R03EB016969 to P.W.A., UMN College of Science and Engineering (R.M.E., P.W.A., P.P.P.) and Masonic Cancer Center (P.P.P.), and grants from the NSF (Career Award 1553255 to P.W.A.), the UMN Institute for Engineering in Medicine (P.P.P., P.W.A.), and the Randy Shaver Research and Community Fund (P.P.P.). A.R. is supported by a UMN Doctoral Dissertation Fellowship. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. We thank Marjorie Carlson for assistance with the KPC mouse models. We thank members of the Provenzano, Alford, and Kim laboratories for technical assistance and insightful comments regarding this work.
© 2017 The Author(s).