Yoshida, Masahiro, Furuyama, Kenichiro, Sumide, Keisuke, Horiguchi, Masashi, Abo-Ahmed, Ahmed I, Shibata, Hirofumi, Tanaka, Akito, Rashwan, Ahmed M, Masui, Toshihiko, Alev, Cantas, Yamamoto, Takuya, Yamada, Yasuhiro, Kaneko, Shin, Narumiya, Shuh, Tuveson, David, Uemoto, Shinji, Hatano, Etsuro, Kawaguchi, Yoshiya (May 2026) Stress-induced CXCL13 regulates pancreatic exocrine homeostasis, age-related chronic inflammation, and cancer progression. Science Advances, 12 (18). eadu7865. ISSN 2375-2548 (Public Dataset)
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Abstract
Pancreatic cancers, whose incidence increases with age, are often refractory to treatment. Here, we identified a core mechanism shared by physiological homeostasis, senescent cell accumulation during aging, and pancreatic cancers. Pancreatic acinar cells, when stressed, secrete CXCL13, which protects stressed cells while transiently activating paracrine Hippo/YAP signaling to induce proliferation and PD-L1-mediated immune protection to maintain organ homeostasis. In the aged pancreas, CXCL13/YAP/PD-L1 signaling permits senescent cells to survive, driving feedforward chronic inflammation and steatosis. Because of prolonged CXCL13/YAP/PD-L1 activation in pancreatic cancers, neighboring noncancerous cells, activated for proliferation and immune-protected, eventually transform and accelerate tumor progression. CXCL13 blockade removed senescent cells and ameliorated steatosis in the aged pancreas while suppressing tumor growth in pancreatic cancer models, highlighting the CXCL13/YAP/PD-L1 axis as a potential therapeutic target. Together, our findings demonstrate the stress-induced CXCL13/YAP/PD-L1 axis as a central regulator of cell-state transitions in the pancreas, providing a unifying principle by which organ homeostasis, aging, and tumorigenesis are governed.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | May 2026 |
| Date Deposited: | 04 May 2026 13:05 |
| Last Modified: | 04 May 2026 13:05 |
| PMCID: | PMC13134631 |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/42188 |
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