Design principles of regulatory networks underlying epithelial mesenchymal plasticity in cancer cells

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Phenotypic plasticity is a hallmark of cancer and drives metastatic disease and drug resistance. The dynamics of epithelial-mesenchymal plasticity is driven by complex interactions involving multiple feedback loops in underlying networks operating at multiple regulatory levels such as transcriptional and epigenetic. The past decade has witnessed a surge in systems-level analysis of structural and dynamical traits of these networks. Here, we highlight the key insights elucidated from such efforts – a) multistability in gene regulatory networks, and the co-existence of many hybrid phenotypes, thus enabling a landscape with multiple “attractors”, b) mutually antagonistic “teams” of genes in these networks, shaping the rates of cell-state transition in this landscape, and c) chromatin-level changes that can alter the landscape, thus controlling reversibility of cell-state transitions, allowing cellular memory in the context of epithelial-mesenchymal plasticity in cancer cells. Such approaches, in close integration with high-throughput longitudinal data, have improved our understanding of the dynamics of cell-state transitions implicated in tumor cell plasticity.