Abstract
Cancer cell migration is influenced by cellular phenotype and behavior as well as by the mechanical and chemical properties of the environment. Furthermore, many cancer cells show plasticity of their phenotype and adapt it to the properties of the environment. Here, we study the influence of fiber stiffness, confinement, and adhesion properties on cancer cell migration in porous collagen gels. Collagen gels with soft fibers abrogate migration and promote a round, non-invasive phenotype. Stiffer collagen fibers are inherently more adhesive and lead to the existence of an adhesive phenotype and in general confined migration due to adhesion. Addition of TGF-β lowers adhesion, eliminates the adhesive phenotype and increases the amount of highly motile amoeboid phenotypes. Highest migration speeds and longest displacements are achieved in stiff collagen fibers in pores of about cell size by amoeboid phenotypes. This elucidates the influence of the mechanical properties of collagen gels on phenotype and subsequently migration and shows that stiff fibers, cell sized pores, and low adhesion, are optimal conditions for an amoeboid phenotype and efficient migration.
Highlights
Migration of cancer cells is a complex process
Their pore size is in a range that does not obstruct migration and the low amount of adhesion sites on the thin HT gel fibers should promote amoeboid migration, these gels entirely abrogate migration even in the presence of TGF
The low fiber stiffness does impair movement itself, and prevents establishment of motile amoeboid phenotypes suggesting that cells react to the stiffness [35] and that motile phenotypes result from a mechanically coupled feedback as discussed in [1]
Summary
Migration of cancer cells is a complex process. It is influenced by properties of the migrating cells as well as their environment [1]. While the environmental properties, such as stiffness, size, and density as well as spatial distribution of adhesion sites, are well controllable for migration on two-dimensional, continuous substrates, these properties are significantly more complex in three-dimensional porous hydrogels [2]. Migration in two dimensions is fairly well understood, but the influence of environmental parameters on three-dimensional migration still remains to be understood [1, 3]. Key parameters of the environment that influence migration in three dimensions are confinement, adhesion sites and stiffness [4, 5]. The influence of adhesion sites depends on cell phenotype.
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