CSB Biology – Professor Bob Fisher, NIH

Cells polarize in response to spatially organized cues from the extracellular matrix (ECM) in the form of contact guidance. Previous work has shown that aligned linear matrices support cell polarization and directional migration. Consistent with this, aligned ECM surrounding primary breast tumors is a strong predictor of metastasis and negative patient outcomes. However, in many cellular environments in vivo in both normal and disease states, collagen and other ECM components are organized into wavy, sinusoidal bundles rather than purely linear fibers. For example, in ovarian stromal tumors, the curvature radii of wavy collagen fibers can vary between 2 and 30 microns, and are predictive of tumor grade.  To investigate how cells polarize on wavy ECMs, we use nanofabrication to create substrates with sinusoidal ridges of approximate cross-section of large collagen fibrils, but of specified curvatures. Using this approach, we have demonstrated that cell polarization and migration is suppressed by cell-scale curvature of ECM fibrils, but not by linear fibrils or short wavelength curvatures, Thus, cells have a minimum curvature they can respond to, dependent on their inherent contractility. While canonical focal adhesion and lamellipodia functions are required to sense the topography, the cell polarization response to topography depends on actomyosin contractility. Our data demonstrate that in addition to soluble and mechanical cues, the extracellular matrix also provides shape-dependent cues to regulate cell polarity and migration.