Fiber Microarchitecture in Interpenetrating Collagen-Alginate Hydrogel with Tunable Mechanical Plasticity Regulates Tumor Cell Migration

The fiber structures of tumor microenvironment (TME) are well-known in regulating tumor cell behaviors, and the plastic remolding of TME has recently been suggested to enhance tumor metastasis as well. However, the interrelationship between the fiber microarchitecture and matrix plasticity are inextricable by existing in vitro models. The individual roles of fiber microarchitecture and matrix plasticity in tuning tumor cell behaviors remain elusive. In this study, we develop a interpenetrating collagen-alginate hydrogel platform with independently tunable matrix plasticity and fiber microarchitecture through an interpenetrating strategy of alginate networks and collagen I networks. With this hydrogel platform, we demonstrate that tumor cells in high plasticity hydrogels are more extensive and aggressive than in low plasticity hydrogels and fiber structures only has influence in high plasticity hydrogels. We further elucidate the underlying mechanisms through analyzing the distribution of forces within the matrix and tracking the focal adhesions (FAs) and find that highly plastic hydrogels can activate the FAs formation, whereas the maturation and stability of FAs are dominated by fiber dispersion. This study not only establishes new ideas on how cells interact with TME cues but also would help to further finely tailor engineered hydrogel platforms for studying tumor behaviors in vitro. This article is protected by copyright. All rights reserved