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

The extracellular matrix (ECM) is a complex network of fibrous proteins and other macro-molecules that provides crucial mechanical and biochemical cues that regulate cancer cell invasion and tumour progression. Its fibre organisation plays a critical role in guiding directional migration through contact guidance, in particular in cancer cell invasion. Mathe-matical modelling offers a powerful approach to explore how the ECM architecture regulates this process. Here, 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 introduce new mechanisms: cell movement direction jointly guided by fibre orientation and chemotaxis, proliferation regulated by oxygen and mechanical pressure, and "cell-front" ECM sensing for both cell movement and ECM remodelling, reflecting protrusion-driven engagement of the matrix. Simulations reveal how initial ECM fibre alignment, anisotropy (fibre-fibre alignment correlation), and reorientation capacity affect cellular invasion, and how competing physical and chemical cues shape the invasive potential of tumour cells. This work provides mechanistic insights into the bidirectional interactions between cancer cells and ECM, highlighting how structural remodelling shapes invasive potential.