Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present with 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 in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY and NPY1R are up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KPR172HC mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout of Npy1r significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPR172HC migratory capacity on cell-derived matrices. Pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing liver met...
| Authors | Chambers, CR; Watakul, S; Schofield, P; Howell, AE; Zhu, J; Tran, AMH; Kuepper, N; Reed, DA; Murphy, KJ; Channon, LM; Pereira, BA; Tyma, VM; Lee, V; Trpceski, M; Henry, J; Melenec, P; Abdulkhalek, L; Nobis, M; Metcalf, XL; Ritchie, S; Cadell, A; Stoehr, J; Magenau, A; Chacon-Fajardo, D; Chitty, JL; O'Connell, S; Zaratzian, A; Tayao, M; Da Silva, A; Lyons, RJ; Goldstein, LD; Dale, A; Rookyard, A; Connolly, A; Crossett, B; Tran, YTH; Kaltzis, P; Vennin, C; Dinevska, M; Australian Pancreatic Cancer Genome Initiative (APGI); Australian Pancreatic Cancer Matrix Atlas (APMA); Croucher, DR; Samra, J; Mittal, A; Weatheritt, RJ; Philp, A; Del Monte-Nieto, G; Zhang, L; Enriquez, RF; Cox, TR; Shi, YC; Pinese, M; Waddell, N; Sim, HW; Chtanova, T; Wang, Y; Joshua, AM; Chantrill, L; Evans, TRJ; Gill, AJ; Morton, JP; Pajic, M; Christ, D; Herzog, H; Timpson, P; Herrmann, D |
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| Journal | Science Advances |
| Pages | eadq4416 |
| Volume | 11 |
| Date | 12/04/2025 |
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| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1126/sciadv.adq4416 |