Targeting the NPY/NPY1R signaling axis in mutant p53–dependent pancreatic cancer impairs metastasis

• DOI: 10.1126/sciadv.adq4416
• Publication Date: 2025-03-12T17:58:57Z
• Authors: Cecilia R. Chambers; Supitchaya Watakul; Peter Schofield; Anna E. Howell; Jessie Zhu; Alice M. H. Tran; Nadia Kuepper; Daniel A. Reed; Kendelle J. Murphy; Lily M. Channon; Brooke A. Pereira; Victoria M. Tyma; Victoria Lee; Michael Trpceski; Jake Henry; Pauline Melenec; Lea Abdulkhalek; Max Nobis; Xanthe L. Metcalf; Shona Ritchie; Antonia Cadell; Janett Stoehr; Astrid Magenau; Diego Chacon-Fajardo; Jessica L. Chitty; Savannah O’Connell; Anaiis Zaratzian; Michael Tayao; Andrew Da Silva; Ruth J. Lyons; Leonard D. Goldstein; Ashleigh Dale; Alexander Rookyard; Angela Connolly; Ben Crossett; Yen T. H. Tran; Peter Kaltzis; Claire Vennin; Marija Dinevska; ; ; David R. Croucher; Jaswinder Samra; Anubhav Mittal; Robert J. Weatheritt; Andrew Philp; Gonzalo Del Monte...; Lei Zhang; Ronaldo F. Enriquez; Thomas R. Cox; Yan-Chuan C. Shi; Mark Pinese; Nicola Waddell; Hao-Wen Sim; Tatyana Chtanova; Yingxiao Wang; Anthony M. Joshua; Lorraine Chantrill; Thomas R. Jeffry ...; Anthony J. Gill; Jennifer P. Morton; Marina Pajic; Daniel Christ; Herbert Herzog; Paul Timpson; David Herrmann
• Keywords: Knockout mouse

Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present advanced-stage disease, preventing potentially curative surgery. The neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis range types, but yet be explored. We show that expression NPY and NPY1R are up-regulated mouse models human PC. Moreover, using the genetically engineered, autochthonous KP R172H C model PC, we demonstrate pancreas-specific whole-body knockout Npy1r significantly decreases metastasis liver. identify treatment antagonist BIBO3304 reduces migratory capacity on cell-derived matrices. Pharmacological inhibition an intrasplenic recapitulated results our genetic studies, decreasing liver metastasis. Together, reveal NPY/NPY1R signaling previously unidentified antimetastatic target