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 tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY and <i>NPY1R</i> are up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KP<sup>R172H</sup>C mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout of <i>Npy1r</i> significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KP<sup>R172H</sup>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.
Authors
- Daniel Christ (ORCID: https://orcid.org/0000-0002-7313-3977)
- Ben Crossett (ORCID: https://orcid.org/0000-0001-5366-4554)
- Alice Tran
- Nicola Waddell (ORCID: https://orcid.org/0000-0002-3950-2476)
- Jennifer P. Morton (ORCID: https://orcid.org/0000-0001-5766-9141)
- Yan‐Chuan Shi (ORCID: https://orcid.org/0000-0002-8368-6735)
- Janett Stoehr (ORCID: https://orcid.org/0000-0002-4198-3520)
- Max Nobis (ORCID: https://orcid.org/0000-0002-1861-1390)
- Mark Pinese (ORCID: https://orcid.org/0000-0001-5078-6687)
- Lea Abdulkhalek
- Thomas R. Jeffry Evans (ORCID: https://orcid.org/0000-0001-5201-885X)
- Jaswinder Singh Samra (ORCID: https://orcid.org/0000-0001-6664-7147)
- Anaiis Zaratzian
- Xanthe L. Metcalf (ORCID: https://orcid.org/0000-0001-9599-9280)
- Claire Vennin (ORCID: https://orcid.org/0000-0001-9088-4177)
- Angela Connolly (ORCID: https://orcid.org/0000-0003-2959-4001)
- Leonard D. Goldstein (ORCID: https://orcid.org/0000-0003-4645-553X)
- Pauline Mélénec (ORCID: https://orcid.org/0000-0001-6486-2003)
- Thi Hai Yen Tran (ORCID: https://orcid.org/0000-0003-1414-2328)
- Andrew Da Silva
- Hao‐Wen Sim (ORCID: https://orcid.org/0000-0002-2530-0523)
- Diego Chacon Fajardo (ORCID: https://orcid.org/0000-0003-3729-1385)
- Robert J. Weatheritt (ORCID: https://orcid.org/0000-0003-3716-1783)
- Andrew Philp (ORCID: https://orcid.org/0000-0003-3860-4136)
- Tatyana Chtanova (ORCID: https://orcid.org/0000-0003-3419-4483)
- Anthony James Gill (ORCID: https://orcid.org/0000-0002-9447-1967)
- Thomas R. Cox (ORCID: https://orcid.org/0000-0001-9294-1745)
- Anubhav Mittal (ORCID: https://orcid.org/0000-0003-3960-2968)
- Alexander W. Rookyard
- Astrid Magenau (ORCID: https://orcid.org/0000-0001-7793-2525)
- Daniel A. Reed (ORCID: https://orcid.org/0000-0002-3736-7725)
- Lily M. Channon (ORCID: https://orcid.org/0000-0002-4456-4233)
- David R. Croucher (ORCID: https://orcid.org/0000-0003-4965-8674)
- Shona Ritchie (ORCID: https://orcid.org/0000-0001-9234-0632)
- Gonzalo del Monte‐Nieto (ORCID: https://orcid.org/0000-0003-3830-2226)
- Michael Tayao (ORCID: https://orcid.org/0000-0001-5224-0784)
- Victoria M. Tyma (ORCID: https://orcid.org/0009-0005-7959-4407)
- Michael Trpceski (ORCID: https://orcid.org/0000-0001-5430-2205)
- Antonia L. Cadell (ORCID: https://orcid.org/0000-0002-3560-4125)
- Paul Timpson (ORCID: https://orcid.org/0000-0002-5514-7080)
- Yingxiao Wang (ORCID: https://orcid.org/0000-0003-0265-326X)
- David Herrmann (ORCID: https://orcid.org/0000-0002-9514-7501)
- Jake Y. Henry (ORCID: https://orcid.org/0000-0003-0435-3308)
- Victoria Lee (ORCID: https://orcid.org/0000-0002-0701-8321)
- Lorraine A. Chantrill (ORCID: https://orcid.org/0000-0002-5790-0208)
- Marina Pajic (ORCID: https://orcid.org/0000-0002-3871-3829)
- Ashleigh Dale
- Kendelle J. Murphy (ORCID: https://orcid.org/0000-0002-3234-3812)
- Cecilia R. Chambers (ORCID: https://orcid.org/0000-0002-4979-9349)
- Marija Dinevska (ORCID: https://orcid.org/0000-0002-0532-1458)
- Brooke Pereira (ORCID: https://orcid.org/0000-0003-3513-1214)
- Anthony M. Joshua (ORCID: https://orcid.org/0000-0001-5159-4580)
- Herbert Herzog
- Jessie Zhu
- Jessica L. Chitty (ORCID: https://orcid.org/0000-0003-1776-1618)
- Peter Kaltzis (ORCID: https://orcid.org/0000-0003-2790-6606)
- Lei Zhang (ORCID: https://orcid.org/0000-0003-1215-6486)
- Anna E. Howell (ORCID: https://orcid.org/0000-0002-6207-182X)
- Peter M. Schofield
- Ruth J. Lyons
- Sean M. O’Connell (ORCID: https://orcid.org/0009-0005-4006-8514)
- Ronaldo F. Enriquez
- Supitchaya Watakul
- Nadia Kuepper
Institutions
- University of Technology Sydney (AU)
- University of Southern California (US)
- The University of Sydney (AU)
- Garvan Institute of Medical Research (AU)
- The University of Melbourne (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Royal North Shore Hospital (AU)
- Centenary Institute (AU)
- Australian Regenerative Medicine Institute (AU)
- Cancer Research UK (GB)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- St Vincent's Hospital Sydney (AU)
- Illawarra Shoalhaven Local Health District (AU)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Children's Cancer Institute Australia (AU)
- St Vincent's Clinic (AU)
- La Jolla Bioengineering Institute (US)
- National Health and Medical Research Council (AU)
- Monash University (AU)
- University of Glasgow (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1126/sciadv.adq4416
- Citations
- 5
- Primary Topic
- Cancer, Stress, Anesthesia, and Immune Response
- Type
- article
- Field-Weighted Citation Impact
- 7.36