Diabetic hyperglycemia-induced glycation regulates tumor vasculature integrity via NF-κB-mediated GM-CSF secretion by tumor cells

Glycation is recognized for its ability to stiffen collagen matrices through non-enzymatic crosslinking. However, the biological effects of glycation in vivo, particularly in diabetic hyperglycemia remain less understood. Clinical observations suggest that diabetes contributes to pathogenic tumor vasculature, yet the underlying mechanisms are not clear. Here, we employed in vitro hydrogels, an ex ovo chicken chorioallantoic membrane model, a mouse model, and RNA sequencing to demonstrate how diabetic hyperglycemia impacts tumor vasculature barrier integrity via glycation-mediated extracellular matrix (ECM) stiffening and production of advanced glycation end-products (AGEs). Stiffened ECM and activated AGE-receptor (RAGE) signaling lead to heightened contractility, activation of nuclear factor κB (NF-κB), increased secretion of granulocyte/macrophage colony-stimulating factor (GM-CSF) in tumor cells, and subsequently, impaired tumor vasculature barrier function. Our findings reveal a novel mechanism by which matrix stiffness and AGE-RAGE signaling synergistically govern vasculature barrier integrity and highlight a key role for matrix stiffness in NF-κB activity.