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

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 tumorig...

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Veröffentlicht in:	Science advances Jg. 11; H. 11; S. eadq4416
Hauptverfasser:	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, 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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Association for the Advancement of Science 14.03.2025
Schlagworte:	Animals Arginine - analogs & derivatives Biomedicine and Life Sciences Cancer Cell Biology Cell Line, Tumor Cell Movement - drug effects Disease Models, Animal Gene Expression Regulation, Neoplastic Humans Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - secondary Mice Mice, Knockout Mutation Neoplasm Metastasis Neuropeptide Y - genetics Neuropeptide Y - metabolism Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Receptors, Neuropeptide Y - antagonists & inhibitors Receptors, Neuropeptide Y - genetics Receptors, Neuropeptide Y - metabolism SciAdv r-articles Signal Transduction - drug effects Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism
ISSN:	2375-2548, 2375-2548
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Zusammenfassung:	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 KP R172H C 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 KP R172H C 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. Targeting NPY1R reduces mutant p53–dependent pancreatic cancer metastasis.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Australian Pancreatic Cancer Genome Initiative (APGI) authors, collaborators, and affiliations are listed in the Supplementary Materials. Australian Pancreatic Cancer Matrix Atlas (APMA) authors, collaborators, and affiliations are listed in the Supplementary Materials.
ISSN:	2375-2548 2375-2548
DOI:	10.1126/sciadv.adq4416