ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy with aggressive metastatic phenotype and very poor clinical prognosis. Interestingly, a lower occurrence of PDAC has been described in individuals with severe and long-standing asthma. Here we gained insight into the potential link between the glucocorticoid (GC) budesonide, a first-line therapy to treat asthma, and PDAC development. We found that in classical 2D setting, budesonide, but not classical GCs, used at high micromolar concentrations, modifies the behavior of PDAC cells, reducing their mesenchymal invasive/migrating features, without altering their proliferation or survival. However, a more physiological 3D environment drives PDAC cells towards a general metabolic reprogramming, which involves protein, lipid, and energy metabolism (e.g., increased glycolysis dependency). Remarkably, this metabolic change sensitizes PDAC cells to an unexpected anti-proliferative action of budesonide, which instead induces opposite metabolic changes (e.g., increased OXPHOS). Under these conditions, budesonide, as dexamethasone and hydrocortisone, inhibits PDAC spheroid growth and proliferation at nanomolar concentrations, in a GR-dependent manner, and through the induction of the tumor suppressor CDKN1C. Collectively, our study uncovers how the growth behavior/conditions influence the susceptibility of PDAC cells to glucocorticoids, and the tumor inhibitory action of budesonide in 3D condition (i.e., organotypic cultures, floating spheroids, and in vivo tumors). Validation in other cancer cells will be necessary to broaden the role of 3D setting and OXPHOS-to-glycolytic transition, in the induction of GC susceptibility. The inhibitory effect of budesonide on in vivo tumors suggests its potential suitability for clinical trials as a novel therapeutic approach to fight pancreatic cancer.
