The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells
Menée à l'aide de lignées cellulaires et de xénogreffes de cancer du pancréas sur des modèles murins, cette étude met en évidence le rôle de la kinase ERK dans l'hétérogénéité de la transition épithélio-mésenchymateuse
Epithelial-mesenchymal transition (EMT) occurs heterogeneously among carcinoma cells to promote chemoresistance. Identifying the signaling pathways involved will nominate drug combinations to promote chemoresponse, but cell population–level studies can be misleading, and single-cell transcriptomics are limited to indirect ontology-based inferences. To understand EMT heterogeneity at a signaling protein level, we combined iterative indirect immunofluorescence imaging of pancreas cancer cells and tumors and mutual information (MI) analysis. Focusing first on mitogen-activated protein kinase pathways, MI indicated that cell-to-cell variation in ERK activity determined EMT heterogeneity in response to different growth factors and chemotherapeutics but that JNK compensated when MEK was inhibited. Population-level models could not capture these experimentally validated MI inferences. The dominant role of ERK was consistently indicated by MI even when the analysis was expanded to include seven potential EMT-regulating signaling nodes. More generally, this work provides an approach for studying multivariate signaling-phenotype relationships based on protein measurements in any setting. Single-cell imaging and information theory reveal key drivers of EMT heterogeneity in pancreatic cancer cells and tumors. Epithelial-mesenchymal transition (EMT) is a process that drives drug resistance and is not uniform among malignant cells in a tumor. Barbeau et al. used mutual information calculations to determine the relationship between signaling activity and EMT marker intensity obtained by single-cell imaging analysis of pancreatic ductal adenocarcinoma (PDAC) cells and tumors. These calculations revealed that EMT heterogeneity in response to growth factors or chemotherapeutics that induce EMT was driven primarily by variations in the activity of the kinase ERK and, when ERK activation was inhibited, by variations in the activity of the related kinase JNK. These findings were robust when mutual information calculations included other signaling molecules and were not uncovered by a bulk biochemical approach or other mathematical approaches. Thus, the addition of ERK inhibitors to PDAC therapy could minimize EMT-induced chemoresistance. —Wei Wong
Science Signaling , résumé, 2025