Dynamical hallmarks of cancer: Phenotypic switching in melanoma and epithelial-mesenchymal plasticity

Abstract

Phenotypic plasticity was recently incorporated as a hallmark of cancer. This plasticity can manifest along many interconnected axes, such as stemness and differentiation, drug-sensitive and drug-resistant states, and between epithelial and mesenchymal cell-states. Despite growing acceptance for phenotypic plasticity as a hallmark of cancer, the dynamics of this process remains poorly understood. In particular, the knowledge necessary for a predictive understanding of how individual cancer cells and populations of cells dynamically switch their phenotypes in response to the intensity and/or duration of their current and past environmental stimuli remains far from complete. Here, we present recent investigations of phenotypic plasticity from a systems-level perspective using two exemplars: epithelial-mesenchymal plasticity in carcinomas and phenotypic switching in melanoma. We highlight how an integrated computational-experimental approach has helped unravel insights into specific dynamical hallmarks of phenotypic plasticity in different cancers to address the following questions: a) how many distinct cell-states or phenotypes exist?; b) how reversible are transitions among these cell-states, and what factors control the extent of reversibility?; and c) how might cell-cell communication be able to alter rates of cell-state switching and enable diverse patterns of phenotypic heterogeneity? Understanding these dynamic features of phenotypic plasticity may be a key component in shifting the paradigm of cancer treatment from reactionary to a more predictive, proactive approach.

Keywords: Cell-cell communication; Cell-state transitions; Epithelial-Mesenchymal Plasticity; Multistability; Phenotypic plasticity; Proliferative-invasive switch.