Diabetes reshapes pancreatic cancer-associated endothelial niche by accelerating senescence

Yu-Wei Ling, Juan-Li Duan, Zi-Jian Jiang, Zhen Yang, Jing-Jing Liu, Ping Song, Zhi-Qiang Fang, Zhen-Sheng Yue, Fei He, Ke-Feng Dou () and Lin Wang ()
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Yu-Wei Ling: Fourth Military Medical University
Juan-Li Duan: Fourth Military Medical University
Zi-Jian Jiang: Fourth Military Medical University
Zhen Yang: Fourth Military Medical University
Jing-Jing Liu: Fourth Military Medical University
Ping Song: Fourth Military Medical University
Zhi-Qiang Fang: Fourth Military Medical University
Zhen-Sheng Yue: Fourth Military Medical University
Fei He: Fourth Military Medical University
Ke-Feng Dou: Fourth Military Medical University
Lin Wang: Fourth Military Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63801-8

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