Single-Cell RNA-Seq Analysis Reveals the Acquisition of Cancer Stem Cell Traits and Increase of Cell-Cell Signaling during EMT Progression

Cancers (Basel). 2021 Nov 16;13(22):5726. doi: 10.3390/cancers13225726.

Abstract

Intermediate cell states (ICSs) during the epithelial-mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several single-cell RNA-seq (scRNA-seq) datasets to investigate the relation between several axes of cancer progression including EMT, CSC traits, and cell-cell signaling. To accomplish this task, we integrate computational methods for clustering and trajectory inference with analysis of EMT gene signatures, CSC markers, and cell-cell signaling pathways, and highlight conserved and specific processes across the datasets. Our analysis reveals that "standard" measures of pluripotency often used in developmental contexts do not necessarily correlate with EMT progression and expression of CSC-related markers. Conversely, an EMT circuit energy that quantifies the co-expression of epithelial and mesenchymal genes consistently increases along EMT trajectories across different cancer types and anatomical locations. Moreover, despite the high context specificity of signal transduction across different cell types, cells undergoing EMT always increased their potential to send and receive signals from other cells.

Keywords: EMT; TGFB; WNT; cancer stem cells; cell–cell signaling; epithelial–mesenchymal plasticity; hybrid E/M; notch; scRNA-seq.