Extracellular nanofiber-orchestrated cytoskeletal reorganization and mediated directional migration of cancer cells

Abstract

Extracellular matrix anisotropy tunes the organization and movement of surrounding cells. The primary mediators of the extracellular matrix are fiber-based materials. Natural collagen fibers reorganize from curled and isotropic fibers to straightened and anisotropic fibers during tumorigenesis, yet how the cytoskeleton is involved in the directional migration in response to the topography is unknown. To investigate this, we fabricated random, orthogonal, and aligned nanofibers to deconstruct the basic mechanisms for the migration of the human pancreatic cancer cells PANC-1 on different substrates. We found that the extracellular matrix orchestrated actin reorganization by templating the surface topography as an irregular pattern on random fibers, crossover feature on orthogonal fibers, and parallel characteristics on aligned fibers. The intermediate filament as vimentin was upregulated to form a perinuclear shape on orthogonal or aligned surfaces. We also found that the nanofiber topography mediated the directional migration via different mechanisms. The directionality ratio and velocity were statistically analyzed to unveil the pattern of directional migration. Cells on aligned nanofibers yielded a greater velocity. Rac1 and Cdc42 were involved in cell migration through regulating actin polymerization and membrane protrusions. Thus, our findings elucidate that nanofiber alignment orchestrates cytoskeletal reorganization and mediates the directional migration of cancer cells.