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

Abstract

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.