To investigate complex biophysical relationships driving directed cell migration, we developed a biomimetic platform that allows perturbation of microscale geometric constraints with concomitant nanoscale contact guidance architectures. This permits us to elucidate the influence, and parse out the relative contribution, of multiscale features, and define how these physical inputs are jointly processed with oncogenic signaling. We demonstrate that collective cell migration is profoundly enhanced by the addition of contract guidance cues when not otherwise constrained. However, while nanoscale cues promoted migration in all cases, microscale directed migration cues are dominant as the geometric constraint narrows, a behavior that is well explained by stochastic diffusion anisotropy modeling. Further, oncogene activation (i.e. mutant PIK3CA) resulted in profoundly increased migration where extracellular multiscale directed migration cues and intrinsic signaling synergistically conspire to greatly outperform normal cells or any extracellular guidance cues in isolation.
Bibliographical noteFunding Information:
This work was supported by the FHCRC/UW Cancer Consortium Cancer Center Support Grant of the National Institutes of Health under Award Number P30CA015704 (to D.H. Kim). Dr. Provenzano was supported by a Research Scholar Grant, RSG-14-171-01-CSM from the American Cancer Society and by the College of Science and Engineering and the Masonic Cancer Center of the University of Minnesota. This work was also supported by grants from the University of Minnesota Institute for Engineering in Medicine (to P.P.P.), the NIH National Cancer Institute under award numbers (R01CA181385 to P.P.P. and P50CA101955 to P.P.P.) and the Randy Shaver Research and Community Fund (to P.P.P.). This research was partially supported by Leading Foreign Research Institute Recruitment Program (2015K1A4A3047345) and Pioneer Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning. The authors thank Dr. Ben Ho Park for providing both parental MCF10A and mutant PIK3CA knockin cell lines.