The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells

Epithelial-mesenchymal transition (EMT) occurs heterogeneously among
malignant carcinoma cells to promote chemoresistance. Identifying the
signaling pathways involved will nominate drug combinations to promote
chemoresponse, but cell population-level studies are inherently fraught,
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 MAP kinase pathways, MI indicated that cell-to-cell variation in
ERK activity dominated control of EMT heterogeneity in response to diverse
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
persistently indicated by MI even when analyzing 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.