Diabetes reshapes pancreatic cancer-associated endothelial niche by accelerating senescence.

Abstract

Approximately half of pancreatic cancer patients present with comorbid diabetes. Diabetes is correlated with adverse prognostic outcomes in pancreatic cancer patients, but the underlying mechanism remains elusive. Here, we demonstrate that the cancer-associated endothelial niche is reshaped in the diabetic pancreatic tumor microenvironment and enhances the tumor-promoting capacity. Senescent endothelial cells expand in the diabetic tumor microenvironment and produce a potential senescence-associated secretory phenotype factor, i.e., INHBB. As a member of the TGF-β superfamily, INHBB promotes tumor progression and is regulated by Notch signaling. Pharmacological inhibition of INHBB receptors with bimagrumab effectively inhibited tumor progression in diabetic mice. Moreover, short-term bimagrumab treatment did not significantly decrease glucose levels in diabetic tumor-bearing mice. Combination treatment with metformin showed synergistic antitumor effects. In conclusion, our study identifies INHBB as a promising therapeutic target for pancreatic cancer with comorbid diabetes, laying the foundation for the development of individualized therapies for pancreatic cancer patients.