IL6R-STAT3 oscillations produce stable heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells

Pro-growth mutations enable malignancy but for proliferation to proceed, energy and substrates cannot be limiting. However, unrestricted metabolic activation would be self-terminating if it depletes tumor resources. Cancer cells could avoid this by alternating between basal and activated metabolic states, thereby producing dynamic, population-level metabolic heterogeneity that rations resources. Single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma cells identified MIA-PaCa-2 as having broad heterogeneity of fermentative metabolism. Cells sorted by greater lactic acid efflux capacity had higher fermentative rates when subsequently cultured. However, this phenotype was unrelated to cell-cycling or glycolytic and respiratory gene expression, and persisted for less than a week. Transcriptomics linked the higher fermentation with IL6R-STAT3 signaling. Accordingly, IL6R-positive cells were more active metabolically. Episodic activation of metabolism arises from delayed negative feedback via SOCS3 on IL6R-STAT3. We propose that switching between metabolic states allows cell-cohorts to take turns in progressing energy-intense processes without over-burdening shared resources. Overall design: RNAseq analysis of FACS sorted subpopulations of MIA PaCa2 cancer cells, representing two extremes of phenotype (a measure of metabolic rate). Repeated four times (i.e. four paired samples).