The interaction between dynamic ligand signaling and epigenetics in Notch-induced cancer metastasis.

Metastatic melanoma presents a formidable challenge in oncology due to its high invasiveness and resistance to current treatments. Central to its ability to metastasize is the Notch signaling pathway, which, when activated through direct cell-cell interactions, propels cells into a metastatic state through mechanisms akin to the epithelial-mesenchymal transition (EMT). While the upregulation of miR-222 has been identified as a critical step in this metastatic progression, the mechanism through which this upregulation persists in the absence of active Notch signaling remains unclear. Here we introduce a dynamical system model that integrates miR-222 gene regulation with histone feedback mechanisms. Through computational analysis spanning both sustained and pulsatile ligand inputs, we delineate the non-linear decision boundaries that govern melanoma cell fate transitions, taking into account the dynamics of Notch signaling and the role of epigenetic modifications. Dimensional analysis reduces the 11-parameter system to three critical control groups governing chromatin modification rates and feedback strengths, providing a theoretical framework for parameter selection in the absence of complete kinetic measurements. Global sensitivity analysis identifies PRC2-mediated methylation and KDM5A-mediated demethylation as the dominant control parameters, while stochastic simulations show population heterogeneity consistent with the variable EMT responses observed in cancer cell populations. Our analysis examines the interplay between Notch signaling pathways and epigenetic regulation in dictating melanoma cell fate.