Abstract

Extracellular matrix (ECM) strongly influences cellular behaviors, including cell proliferation, adhesion, and particularly migration. In cancer, the rigidity of the stromal collagen environment is thought to control tumor aggressiveness, and collagen alignment has been linked to tumor cell invasion. While the mechanical properties of collagen at both the single fiber scale and the bulk gel scale are quite well studied, how the fiber network responds to local stress or deformation, both structurally and mechanically, is poorly understood. This intermediate scale knowledge is important to understanding cell-ECM interactions and is the focus of this study. We have developed a three-dimensional elastic collagen fiber network model (bead-and-spring model) and studied fiber network behaviors for various biophysical conditions: collagen density, crosslinker strength, crosslinker density, and fiber orientation (random vs. prealigned). We found the best-fit crosslinker parameter values using shear simulation tests in a small strain region. Using this calibrated collagen model, we simulated both shear and tensile tests in a large linear strain region for different network geometry conditions. The results suggest that network geometry is a key determinant of the mechanical properties of the fiber network. We further demonstrated how the fiber network structure and mechanics evolves with a local formation, mimicking the effect of pulling by a pseudopod during cell migration. Our computational fiber network model is a step toward a full biomechanical model of cellular behaviors in various ECM conditions.

Highlights

  • Extracellular matrix (ECM), the extracellular part of multicellular structure, provides mechanical support and physical separation to tissues [1,2], and regulates key biological processes including development, differentiation, and wound healing [3,4,5]

  • Assuming that the viscous effect of collagen gels is negligible in the slow strain rate region that is relevant to cell migration, we focus on the elastic effect of collagen gels using our elastic fiber network model

  • We have developed an elastic fiber network model of aligned and random collagen networks that contains explicit elastic inter-fiber crosslinkers

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Summary

Introduction

Extracellular matrix (ECM), the extracellular part of multicellular structure, provides mechanical support and physical separation to tissues [1,2], and regulates key biological processes including development, differentiation, and wound healing [3,4,5]. ECM dynamically communicates with cells by chemical and mechanical signals [6,7,8,9,10]. As a major component of the tumor microenvironment, the ECM regulates cancer cell proliferation and invasion into the stroma [11,12]. The main component of ECM in the breast, is observed be denser in breast tumor tissue [12,13,14]. The role of stromal collagen deposition in cancer is a topic of recent intense study, due to the association with aggressive cancer behaviors [11,12,13,14,15,16]

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