Cancer cell migration through and away from tumors is driven in part by migration along aligned extracellular matrix, a process known as contact guidance (CG). To concurrently study the influence of architectural and mechanical regulators of CG sensing, we developed a set of CG platforms. Using flat and nanotextured substrates with variable architectures and stiffness, we show that CG sensing is regulated by substrate stiffness and define a mechanical role for microtubules and actomyosin-microtubule interactions during CG sensing. Furthermore, we show that Arp2/3-dependent lamellipodia dynamics can compete with aligned protrusions to diminish the CG response and define Arp2/3- and Formins-dependent actin architectures that regulate microtubule-dependent protrusions, which promote the CG response. Thus, our work represents a comprehensive examination of the physical mechanisms influencing CG sensing. Aligned extracellular matrix architectures in tumors direct migration of invasive cancer cells. Tabdanov et al. show that the mechanical properties of aligned extracellular matrix environments influence invasive cell behavior and define a mechanical role for microtubules and actomyosin-microtubule interactions during sensing of contact guidance cues that arise from aligned extracellular matrix.
Bibliographical noteFunding Information:
P.P.P. and this work were supported by a Research Scholar Grant (RSG-14-171-01-CSM) from the American Cancer Society and by the NIH ( U54CA210190 University of Minnesota Physical Sciences in Oncology Center Project 2 to P.P.P., R01CA181385 to P.P.P., and R01CA181385S1 to E.D.T. and P.P.P.), UMN College of Science and Engineering (P.P.P.), Masonic Cancer Center (P.P.P.), and grants from the UMN Institute for Engineering in Medicine (P.P.P.) and the Randy Shaver Research and Community Fund (P.P.P.). 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. The University Imaging Center ( http://uic.umn.edu ) at the University of Minnesota facilitates use of the Nikon A1Rsi Confocal microscope and its integral 2D and 3D image analysis software (NIS-Elements Confocal, NIS-Elements Confocal Advanced Research). We thank University Imaging Center staff, and in particular Dr. Guillermo Marques, for helpful assistance. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network (NNCI) under Award ECCS-1542202 . We thank Zaw Win for helpful assistance with imaging. We thank the members of the Provenzano laboratory for insightful comments regarding this work.
- carcinoma metastasis
- contact guidance