Science advances · 2025

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

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Chambers Cecilia R, Watakul Supitchaya, Schofield Peter, Howell Anna E, Zhu Jessie, Tran Alice M H, Kuepper Nadia, Reed Daniel A, Murphy Kendelle J, Channon Lily M, Pereira Brooke A, Tyma Victoria M, Lee Victoria, Trpceski Michael, Henry Jake, Melenec Pauline, Abdulkhalek Lea, Nobis Max, Metcalf Xanthe L, Ritchie Shona, Cadell Antonia, Stoehr Janett, Magenau Astrid, Chacon-Fajardo Diego, Chitty Jessica L, O'Connell Savannah, Zaratzian Anaiis, Tayao Michael, Da Silva Andrew, Lyons Ruth J, Goldstein Leonard D, Dale Ashleigh, Rookyard Alexander, Connolly Angela, Crossett Ben, Tran Yen T H, Kaltzis Peter, Vennin Claire, Dinevska Marija, Australian Pancreatic Cancer Genome Initiative (APGI), Australian Pancreatic Cancer Matrix Atlas (APMA), Croucher David R, Samra Jaswinder, Mittal Anubhav, Weatheritt Robert J, Philp Andrew, Del Monte-Nieto Gonzalo, Zhang Lei, Enriquez Ronaldo F, Cox Thomas R, Shi Yan-Chuan C, Pinese Mark, Waddell Nicola, Sim Hao-Wen, Chtanova Tatyana, Wang Yingxiao, Joshua Anthony M, Chantrill Lorraine, Evans Thomas R Jeffry, Gill Anthony J, Morton Jennifer P, Pajic Marina, Christ Daniel, Herzog Herbert, Timpson Paul, Herrmann David

Аннотация

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 metastasis. Together, our results reveal that NPY/NPY1R signaling is a previously unidentified antimetastatic target in PC.

Предметные рубрики MeSH

Pancreatic Neoplasms Animals Receptors, Neuropeptide Y Neuropeptide Y Humans Signal Transduction Mice Tumor Suppressor Protein p53 Cell Line, Tumor Liver Neoplasms Neoplasm Metastasis Disease Models, Animal Mutation Gene Expression Regulation, Neoplastic Mice, Knockout Cell Movement Arginine

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

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Аннотация

Предметные рубрики MeSH