Context-dependent effect of glucocorticoid receptor activity shapes ovarian cancer cell plasticity and therapy response

The phenotypic plasticity of cancer cells, i.e. their adaptability to a variable/ stressful environment, is fundamental for disease progression/aggressiveness. Here we revealed that the glucocorticoid receptor (GR, NR3C1), a key player in the human response to stress, controls proliferation, morphology, motility/invasion, and the gene expression profile of high-grade serous ovarian carcinoma (hereafter OC) cells. By modulating glucose metabolism, GR acts as a tumor suppressor delaying ovarian cancer growth under 3D-settings. Conversely, under 2D conditions GR acts as a tumor promoter, driving cell mesenchymalization, increasing cell motility and chemoresistance. Strikingly, modulators of glucose metabolism as metformin and 2-deoxyglucose, are alone sufficient to induce similar cell behavioural changes. So, in ovarian cancer a GR-glucose metabolism axis modulates a escaping signalling response triggered by stressful (3D overgrowth, starvation) condition.