A quantitative model for the emergent population dynamics of the melanoma MITF rheostat

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Original abstract

Cancer progression is driven by the ability of cells with identical driver mutations to adopt biologically distinct adaptive phenotypes. Yet the population dynamics implied by intratumour phenotypic heterogeneity is poorly understood. Melanoma, a highly aggressive skin cancer, represents an excellent model to explore phenotype-switching, in part because phenotypic identity is conferred by melanocyte-associated transcription factor (MITF) activity. Here we develop and analyse a multiscale phenotype-structured PDE model for melanoma cell populations in the epidermis, progressing from subcellular MITF dynamics to well-mixed and radially resolved population models. Numerical solutions revealed that the model admits three distinct and stable long-term population behaviours: a slow-growing melanoma of proliferative cells and non-cycling, differentiated cells without invasive potential; a faster-propagating melanoma with an invasive core; and a rapidly growing melanoma with oscillatory core dynamics. More broadly, the analysis also highlights that phenotype reversibility by individual cells does not imply reversibility of phenotype distributions at the population scale. Hence, properties at the single-cell level (e.g., reversibility of invasive capacity) must be extrapolated with caution to populations with coupled cell dynamics. These findings further the understanding of melanoma population dynamics and cell plasticity more generally.

Links and sources

• Official / arXiv page
• PDF from original source

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