Glutathione Peroxidase 8 (GPX8)-IL-6 axis as a regulator of cancer stemness

Tumor cells rewire their cellular metabolism in order to supply building blocks needed to support their rapid proliferation and growth. However, how these alternations promote cancer cell transition to the aggressiveness state is still unclear. Previously we identified a “mesenchymal metabolic signature”, a set of metabolic genes whose expression highly correlated with known mesenchymal markers. Among them is glutathione peroxidase 8 (GPX8), an endoplasmic reticulum transmembrane protein, whose physiological function is still unclear. Here, we assess the role of GPX8 as a regulator of cancer cell aggressiveness. We find that the epithelial-to-mesenchymal (EMT) program regulates GPX8 expression and high expression levels correlate with poor patient outcome. Moreover, GPX8 knockout in the mesenchymal-like cells results in an epithelial-like morphology, downregulation of EMT characteristics, loss of cancer stemness features, and tumor initiation in mice. We identify that GPX8 mediates its cancer-related function by regulating the production of crucial autocrine factors promoting tumor aggressiveness such as IL-6. Specifically, GPX8 loss results in the inhibition of IL6 trans-signaling, mediated by the soluble IL6 receptor, which fails to activate the JAK2-STAT3 signaling pathway. Together, our findings identify the metabolic enzyme GPX8 as a robust regulator of cancer cell aggressiveness.