A hybrid computational model of cancer spheroid growth with ribose-induced collagen stiffening

Margherita Botticelli ¹ John Metzcar ² Thomas Phillips ³ Susan Cox ³ Pradeep Keshavanarayana ^1,4* Fabian Spill ^1*

• ¹ School of Mathematics, College of Engineering and Physical Sciences, University of Birmingham, Birmingham, England, United Kingdom
• ² Department of Intelligent Systems Engineering, Luddy School of Informatics, Computing and Engineering, Indiana University Bloomington, Bloomington, Indiana, United States
• ³ Randall Centre for Cell & Molecular Biophysics, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, England, United Kingdom
• ⁴ University College London, London, England, United Kingdom

Metastasis, the leading cause of death in cancer patients, arises when cancer cells disseminate from a primary solid tumour to distant organs. Growth and invasion of the solid tumour often involve collective cell migration, which is profoundly influenced by cell-cell interactions and the extracellular matrix (ECM). The ECM's biochemical composition and mechanical properties, such as stiffness, regulate cancer cell behaviour and migration dynamics. Mathematical modelling serves as a pivotal tool for studying and predicting these complex dynamics, with hybrid discrete-continuous models offering a powerful approach by combining agent-based representations of cells with continuum descriptions of the surrounding microenvironment. In this study, we investigate the impact of ECM stiffness, modulated via ribose-induced collagen cross-linking, on cancer spheroid growth and invasion. We employed a hybrid discrete-continuous model implemented in PhysiCell to simulate spheroid dynamics, successfully replicating three-dimensional in vitro experiments. The model incorporates detailed representations of cell-cell and cell-ECM interactions, ECM remodelling, and cell proliferation. Our simulations align with experimental observations of two breast cancer cell lines, non-invasive MCF7 and invasive HCC1954, under varying ECM stiffness conditions. The results demonstrate that increased ECM stiffness due to ribose-induced cross-linking inhibits spheroid invasion in invasive cells, whereas non-invasive cells remain largely unaffected. Furthermore, our simulations show that higher ECM degradation by the cells not only enables spheroid growth and invasion but also facilitates the formation of multicellular protrusions. Conversely, increasing the maximum speed that cells can reach due to cell-ECM interactions enhances spheroid growth while promoting single-cell invasion. This hybrid modelling approach enhances our understanding of the interplay between cancer cell migration, proliferation, and ECM mechanical properties, paving the way for future studies incorporating additional ECM characteristics and microenvironmental conditions.