Adhesion-driven invasion: disentangling the interplay between cell-cell and cell-matrix interactions in cancer cell migration

Metastasis proceeds through the dissemination of cells from the primary tumor into the surrounding extracellular matrix (ECM), initiating further spread throughout the body. The invasion of cancer cells into the ECM is significantly influenced by cell-cell adhesion, cell-matrix adhesion, and the generation of traction forces. However, the complex interplay between these different aspects makes it difficult to disentangle their roles in the invasive process, hampering our mechanistic understanding of collective cell invasion. Here, we combine integrin knockout experiments in Hs578T and 4T1 breast cancer cell lines with a computational cellular Potts model to elucidate the biophysical mechanisms underlying invasive cell behavior. By tuning the cell-cell and cell-matrix adhesion parameters in our computational model, we establish a quantitative mapping with the experiments. Our work reveals that strong cell-matrix interactions promote invasion, while strong cell-cell adhesion promotes the formation and dissemination of multicellular clusters. Moreover, our model delineates a threshold for invasion and predicts that tumor morphology – particularly the number of branches from the primary tumor – correlates with its invasive potential, suggesting that morphological tumor features may serve as a proxy for metastasis. Our approach highlights the importance of combining biological experiments with computational and predictive modeling, offering new insights into the mechanisms driving cancer cell migration.