Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la perte de l'expression de la glutathion peroxydase 2 dans les cellules mammaires cancéreuses favorise la plasticité métabolique de ces dernières et la progression tumorale
Redox regulation of breast cancer underlies malignant progression. Loss of the antioxidant glutathione peroxidase 2 in breast cancer cells increases reactive oxygen species, thereby activating hypoxia inducible factor-α (HIF1α) signaling. This in turn causes vascular malfunction, resulting in hypoxia and metabolic heterogeneity. HIF1α suppresses oxidative phosphorylation and stimulates glycolysis (the Warburg effect) in most of the tumor, except for one cancer subpopulation, which was capable of using both metabolic modalities. Hence, adopting a hybrid metabolic state may allow tumor cells to survive under aerobic or hypoxic conditions, a vulnerability that may be exploited for therapeutic targeting by either metabolic or redox-based strategies.In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.The single cell RNA sequencing data reported in this paper have been deposited and publicly released in the Gene Expression Omnibus database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE152368). Coding analyses for single cell RNA sequencing data are available in GitHub with the URL accession link https://github.com/Malindrie/Breast-cancer-scRNA-seq-analysis. All other study data are included in the main text and SI Appendix.