1. T. Chen, M. A. Al-Radhawi, H. Levine, and E. D. Sontag. The interaction between dynamic ligand signaling and epigenetics in Notch-induced cancer metastasis. 2025. Note: Submitted. Also biorxiv 10.1101/2025.05.19.654987. Keyword(s): metastasis, melanoma, Notch signaling, miR-222, epigenetics. Abstract:

   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, 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. Our approach highlights the critical interplay between Notch signaling pathways and epigenetic regulation in dictating the fate of melanoma cells.




2. M.A. Al-Radhawi, S. Tripathi, Y. Zhang, E.D. Sontag, and H. Levine. Epigenetic factor competition reshapes the EMT landscape. Proc Natl Acad Sci USA, 119:e2210844119, 2022. [WWW] [PDF] Keyword(s): gene networks, Epithelial-Mesenchymal Transition, EMT, epigenetics, systems biology, cancer. Abstract:

   The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as Gene Regulatory Networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. In this paper, we propose a conceptual and mathematical modeling framework that incorporates both local and global competition effects between antagonistic epigenetic regulators in addition to local transcription factors, and show the counter-intuitive consequences of such interactions. We apply our approach to recent experimental findings on the Epithelial-Mesenchymal Transition (EMT). We show that it can explain the puzzling experimental data as well provide new verifiable predictions.

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