Dynamics of Epithelial-Mesenchymal Plasticity: What Have Single-Cell Investigations Elucidated So Far?

Epithelial-mesenchymal plasticity (EMP) is a key driver of cancer metastasis and therapeutic resistance, through which cancer cells can reversibly and dynamically alter their molecular and functional traits along the epithelial-mesenchymal spectrum. While cells in the epithelial phenotype are usually tightly adherent, less metastatic, and drug-sensitive, those in the hybrid epithelial/mesenchymal and/or mesenchymal state are more invasive, migratory, drug-resistant, and immune-evasive. Single-cell studies have emerged as a powerful tool in gaining new insights into the dynamics of EMP across various cancer types. Here, we review many recent studies that employ single-cell analysis techniques to better understand the dynamics of EMP in cancer both in vitro and in vivo. These single-cell studies have underlined the plurality of trajectories cells can traverse during EMP and the consequent heterogeneity of hybrid epithelial/mesenchymal phenotypes seen at both preclinical and clinical levels. They also demonstrate how diverse EMP trajectories may exhibit hysteretic behavior and how the rate of such cell-state transitions depends on the genetic/epigenetic background of recipient cells, as well as the dose and/or duration of EMP-inducing growth factors. Finally, we discuss the relationship between EMP and patient survival across many cancer types. We also present a next set of questions related to EMP that could benefit much from single-cell observations and pave the way to better tackle phenotypic switching and heterogeneity in clinic.