Abstract
Epithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) formation are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose 'stemness'. This plasticity in cell states is modulated by signaling pathways such as Notch. However, the interconnections among the cell states enabled by EMT, CSCs and Notch signaling remain elusive. Here, we devise a computational model to investigate the coupling among the core decision-making circuits for EMT, CSCs and Notch. Our model predicts that hybrid E/M cells are most likely to associate with stem-like traits and enhanced Notch-Jagged signaling – a pathway implicated in therapeutic resistance. Further, we show that the position of the 'stemness window' on the 'EMT axis' is varied by altering the coupling strength between EMT and CSC circuits, and/or modulating Notch signaling. Finally, we analyze the gene expression profile of CSCs from several cancer types and observe a heterogeneous distribution along the 'EMT axis', suggesting that different subsets of CSCs may exist with varying phenotypes along the epithelial-mesenchymal axis. We further investigate therapeutic perturbations such as treatment with metformin, a drug associated with decreased cancer incidence and increased lifespan of patients. Our mechanism-based model explains how metformin can both inhibit EMT and blunt the aggressive potential of CSCs simultaneously, by driving the cells out of a hybrid E/M stem-like state with enhanced Notch-Jagged signaling.
Highlights
Metastatic spread of cancer cells claims the highest number of fatalities, accounting for over 90% of cancer-related deaths [1]
Studies in mouse models have suggested that a large percentage of metastases are formed by clusters of Circulating Tumor Cells (CTCs) – cohesive units of two or more CTCs that are launched into the bloodstream as aggregates [2]
As the first step to investigate the coupling among states of Notch signaling, Epithelial-mesenchymal transition (EMT), and stemness (i.e. STEM module), we examined how an epithelial cell responds to varying levels of external Notch ligands LEXT
Summary
Metastatic spread of cancer cells claims the highest number of fatalities, accounting for over 90% of cancer-related deaths [1]. To enter the bloodstream as clusters of CTCs, epithelial cancer cells in primary solid tumors typically partially lose their cell-cell adhesion with their neighbors, and simultaneously acquire mesenchymal traits of motility and invasion. Modulation by external signaling pathways can decouple the abovementioned correlation, suggesting that stem-like traits need not be exclusively correlated with a specific EMT phenotype. To validate this prediction, we examine the gene expression profile of CSCs from several cancer subtypes and find a heterogeneous distribution for the ‘stemness window’ along the ‘EMT axis’, enabling the existence of subsets of CSCs with epithelial, hybrid E/M or mesenchymal phenotypes. We apply our formalism to model the action of metformin in targeting CSCs and inhibiting EMT, providing a mechanism-based explanation for several experimental findings, including decreased Notch levels in metformin-treated pancreatic cancer cells [26], metformin inhibition of TGF-beta induced EMT [27] and the recovery of stem-like traits upon NF-κB overexpression in metformin-treated cells [28]
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