Durotaxis and extracellular matrix degradation promote clustering of cancer cells

Early stages of metastasis depend on the collective behavior of cancer cells and their interaction 23 with the extracellular matrix (ECM). Cancer cell clusters are known to exhibit higher metastatic 24 potential than single cells. To explore clustering dynamics, we developed a calibrated computa- 25 tional model describing how motile cancer cells biochemically and biomechanically interact with 26 the ECM during the initial invasion phase, including ECM degradation and mechanical remod- 27 eling. The model reveals that cluster formation time, size, and shape are influenced by ECM 28 degradation rates and cellular responsiveness to external stresses (durotaxis). The results align 29 with experimental observations, demonstrating distinct cell trajectories and cluster morphologies 30 shaped by biomechanical parameters. These simulations provide valuable insights into cancer 31 invasion dynamics and may suggest potential therapeutic strategies targeting early-stage inva- 32 sive cells.