The role of contact guidance and ECM remodelling in cancer invasion: a computational study

Abstract

The extracellular matrix (ECM) is a complex network of fibrous proteins and other macromolecules that provides both structural support and directional cues that regulate cancer cell invasion and tumour progression. Its fibre organisation plays a critical role in directing migration through contact guidance, while cancer cells simultaneously remodel the matrix through biochemical and mechanical interactions. However, the interplay between ECM architecture, chemical gradients, and matrix remodelling remains poorly understood. Mathematical modelling offers a powerful approach to explore how ECM architecture regulates this process. We present a hybrid computational model, implemented in PhysiCell, that integrates a discrete agent-based cell model with a continuous representation of the chemical microenvironment and ECM microstructure. In an advance over previous efforts, we adapt several mechanisms to a fibre-focused representation of the ECM, including "cell-front" ECM sensing reflecting protrusion-driven engagement of the matrix, contact-guided cell movement via ECM fibre orientation integrated with chemotaxis bias, and proliferation regulated by oxygen and mechanical pressure. In addition, we introduce a new mechanical mechanism for ECM density displacement alongside degradation to simulate how cells redistribute matrix fibres. Simulations reveal how the interplay between initial fibre alignment, anisotropy (fibre-fibre alignment correlation), and fibre reorientation capacity affects invasion, and how competing mechanical and chemical cues influence the invasive potential of tumour cells. Furthermore, our results demonstrate that the balance between degradation and displacement strongly affects invasion dynamics, with high displacement promoting the formation of dense ECM rims around tumour spheroids, whereas increased degradation enables greater invasive spread. This work provides mechanistic insights into bidirectional interactions between cancer cells and the surrounding ECM, highlighting how structural remodelling of the ECM influences the invasive potential of cancer cells. Author summaryCancer cells invade surrounding tissue by interacting with the extracellular matrix (ECM), a fibrous network of proteins that provides both mechanical support and directional cues for migration. Experiments have shown that the orientation of ECM fibres can either promote or hinder invasion, but it remains difficult to disentangle the underlying mechanisms because cells both respond to and actively remodel the matrix. To address this challenge, we developed a computational model that simulates how cancer cells migrate through and reshape the ECM. The model combines individual cell behaviour with a representation of ECM structure, including fibre orientation, anisotropy (fibre-fibre alignment correlation), and density. Our simulations show that invasion depends on the initial fibre orientation and on chemical cues. We also introduce a mechanism that allows cells to mechanically displace the matrix, revealing how the balance between matrix degradation and physical pushing can generate either compact tumour growth or sparse invasion. These results help explain how physical interactions between cells and their environment shape tumour invasion. More broadly, the framework provides a tool to explore how mechanical and chemical signals together regulate collective cell migration in cancer and other biological systems.