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Simple Summary  Phenotypic plasticity is emerging as a crucial feature across multiple axes of cancer progression. Cells undergoing the epithelial–mesenchymal transition (EMT) can fall into intermediate or hybrid epithelial/mesenchymal (E/M) cell states. Moreover, cancer cells across the EMT spectrum can exhibit the traits of cancer stem cells (CSCs) and communicate through several cell-cell signaling pathways. By integrating multiple analytical tools into a single computational framework, we investigated several single-cell RNA-sequencing (scRNA-seq) datasets and identified the emerging relationship between EMT, acquisition of CSC traits, and cell–cell communication. Our integrated analysis shows that the increase of EM plasticity correlates with high expression of CSC markers as well as intensification of cell–cell signaling between cancer cells. Furthermore, these observations are consistent across different cancer types and anatomical locations. Overall, our results shine light onto the interconnected and multi-dimensional landscape of cancer progression.    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.

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