title: Plasticity of the actin cytoskeleton in response to extracellular matrix nanostructure and dimensionality.
abstract: Mobile cells discriminate and adapt to mechanosensory input from extracellular matrix (ECM) topographies to undergo actin-based polarization, shape change and migration. We tested 'cell-intrinsic' and adaptive components of actin-based cell migration in response to widely used in vitro collagen-based substrates, including a continuous 2D surface, discontinuous fibril-based surfaces (2.5D) and fibril-based 3D geometries. Migrating B16F1 mouse melanoma cells expressing GFP-actin developed striking diversity and adaptation of cytoskeletal organization and migration efficacy in response to collagen organization. 2D geometry enabled keratinocyte-like cell spreading and lamellipod-driven motility, with barrier-free movement averaging the directional vectors from one or several leading edges. 3D fibrillar collagen imposed spindle-shaped polarity with a single cylindrical actin-rich leading edge and terminal filopod-like protrusions generating a single force vector. As a mixed phenotype, 2.5D environments prompted a broad but fractalized leading lamella, with multiple terminal filopod-like protrusions engaged with collagen fibrils to generate an average directional vector from multiple, often divergent, interactions. The migratory population reached >90% of the cells with high speeds for 2D, but only 10-30% of the cells and a 3-fold lower speed range for 2.5D and 3D substrates, suggesting substrate continuity as a major determinant of efficient induction and maintenance of migration. These findings implicate substrate geometry as an important input for plasticity and adaptation of the actin cytoskeleton to cope with varying ECM topography and highlight striking preference of moving cells for 2D continuous-shaped over more complex-shaped discontinuous 2.5 and 3D substrate geometries.
authors.affiliation: *Department of Dermatology, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
authors.forename: Josefine
authors.initials: J
authors.lastname: Starke
authors.affiliation: †Institute of Pathology, University of Geneva, Geneva, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wehrle-Haller
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002465:Cell Movement; D055598:Chemical Phenomena; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D055595:Mechanical Phenomena; D008954:Models, Biological; D011554:Pseudopodia / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure