Quantifying the effect of phenotype on clustering behaviour in melanoma: from monoculture to co-culture

Abstract: Melanoma is an aggressive form of skin cancer. Survival rates are excellent if it is detected early but fall markedly if it metastasises. A key step in early tumour progression is the formation of cell clusters, which can promote metastasis. However, the mechanisms driving cell clustering, and the role of phenotypic heterogeneity in the dynamics of these clusters, remain poorly understood. In this work, we propose a system of ordinary differential equations that models cluster formation dynamics within a coagulation-fragmentation-proliferation framework. Using Bayesian inference, we fit this model to in vitro time-lapse microscopy data from two melanoma phenotypes-proliferative and invasive-to uncover the predominant mechanisms driving cluster formation and how these differ between phenotypes. Additionally, we provide preliminary insights into how clustering behaviour in co-cultures contrasts with that observed in monocultures. The model quantifies phenotypic differences in clustering dynamics: invasive cells in monoculture exhibit nearly threefold higher coagulation rates than proliferative cells, whereas proliferative cells display slightly higher proliferation rates. These differences align with known gene expression profiles. When applied to co-culture data, the model predicts hybrid coagulation behaviour of the clusters influenced by both proliferative and invasive cells but dominated by the invasive cells, and an elevated proliferation rate, suggesting a mutually beneficial effect of phenotypic heterogeneity on cell proliferation.