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. 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).