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

Abstract

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.

SpottedPy quantifies relationships between spatial transcriptomic hotspots and uncovers new environmental cues of epithelial-mesenchymal plasticity in cancer

“…Delving deeper into EMT, we observed that hybrid EMT states exhibit more heterogeneous and weaker associations with the TME in comparison to the quasi-mesenchymal M1 state. This disparity might be indicative of the inherent plasticity of hybrid EMT states 75,76 , complicating our ability to delineate clear relationships, but also of a directed trajectory towards an M1 state. The M2 state demonstrates relatively weaker connections with the TME, which may be attributed to the experimental gain of integrin β4 (a key epithelial marker) when cultured, a limitation mentioned in the original study which potentially transformed the state towards a more epithelial phenotype 40 .…”

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…Fibrosis is often associated with pathologies characterized by a chronic inflammatory state, such as autoimmune diseases or tumors. In these circumstances, the prolonged release of growth factors and/or pro-inflammatory factors such as transforming growth factor-β (TGF-β) or various cytokines mediate the activation of a cellular transformation process called epithelial–mesenchymal plasticity (EMP) [ 5 ]. When EMP is activated, the epithelial cells, which have a phenotype of adherent cells closely connected to each other and are not invasive, become transformed, assuming a hybrid epithelial/mesenchymal phenotype and/or a completely mesenchymal phenotype.…”

“…When EMP is activated, the epithelial cells, which have a phenotype of adherent cells closely connected to each other and are not invasive, become transformed, assuming a hybrid epithelial/mesenchymal phenotype and/or a completely mesenchymal phenotype. In this case, the process is defined as epithelial-to-mesenchymal transition (EMT) [ 5 ]. These cells acquire much higher migratory capabilities and are able to deposit extracellular matrix (ECM) proteins.…”

Epithelial–mesenchymal plasticity in cancer: signaling pathways and therapeutic targets

“…Phenotypic plasticity, the ability that tumor cells gain various malignant phenotypes to better survive in the dynamically varying environment, is thought as the critical hallmark of tumor deterioration. 1 Epithelial–mesenchymal plasticity (EMP) is one of the classically well‐studied manifestations of phenotypic plasticity during tumor progression. 2 EMP represents the reversible switch of tumor cells from epithelial phenotype to partially or fully mesenchymal phenotype, including epithelial–mesenchymal transition (EMT), partial EMT (p‐EMT), and mesenchymal–epithelial transition (MET), which are observed during the process of tumor progression.…”