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

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; Australian Pancreatic Cancer Genome Initiative (APGI); Australian Pancreatic Cancer Matrix Atlas (APMA); David R Croucher; Jaswinder Samra; Anubhav Mittal; Robert J Weatheritt; Andrew Philp; Gonzalo Del Monte-Nieto; 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 Evans; Anthony J Gill; Jennifer P Morton; Marina Pajic; Daniel Christ; Herbert Herzog; Paul Timpson; David Herrmann

doi:10.1126/sciadv.adq4416

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

Sci Adv. 2025 Mar 14;11(11):eadq4416. doi: 10.1126/sciadv.adq4416. Epub 2025 Mar 12.

Authors

Cecilia R Chambers^{1

2}, Supitchaya Watakul¹, Peter Schofield^{1

2

3}, Anna E Howell¹, Jessie Zhu^{1

2}, Alice M H Tran¹, Nadia Kuepper¹, Daniel A Reed^{1

2}, Kendelle J Murphy^{1

2}, Lily M Channon¹, Brooke A Pereira^{1

2}, Victoria M Tyma¹, Victoria Lee¹, Michael Trpceski^{1

2}, Jake Henry^{1

2

3}, Pauline Melenec¹, Lea Abdulkhalek¹, Max Nobis^{1

2

4}, Xanthe L Metcalf¹, Shona Ritchie^{1

2}, Antonia Cadell^{1

2

5}, Janett Stoehr¹, Astrid Magenau^{1

2}, Diego Chacon-Fajardo^{1

2

5}, Jessica L Chitty^{1

2}, Savannah O'Connell³, Anaiis Zaratzian¹, Michael Tayao¹, Andrew Da Silva¹, Ruth J Lyons¹, Leonard D Goldstein^{2

6}, Ashleigh Dale⁷, Alexander Rookyard⁷, Angela Connolly⁷, Ben Crossett⁷, Yen T H Tran⁸, Peter Kaltzis⁸, Claire Vennin^{1

2}, Marija Dinevska^{1

9

10}; Australian Pancreatic Cancer Genome Initiative (APGI); Australian Pancreatic Cancer Matrix Atlas (APMA); David R Croucher^{2

5}, Jaswinder Samra¹¹, Anubhav Mittal¹¹, Robert J Weatheritt³, Andrew Philp^{12

13}, Gonzalo Del Monte-Nieto⁸, Lei Zhang^{2

14}, Ronaldo F Enriquez^{1

2}, Thomas R Cox^{1

2}, Yan-Chuan C Shi^{1

2}, Mark Pinese^{2

15}, Nicola Waddell¹⁶, Hao-Wen Sim^{1

2

17}, Tatyana Chtanova^{1

18}, Yingxiao Wang^{19

20}, Anthony M Joshua^{2

5}, Lorraine Chantrill²¹, Thomas R Jeffry Evans^{22

23}, Anthony J Gill^{1

11

24}, Jennifer P Morton^{22

23}, Marina Pajic^{2

5}, Daniel Christ^{1

2

3}, Herbert Herzog^{2

14}, Paul Timpson^{1

2}, David Herrmann^{1

2}

Affiliations

¹ Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, Sydney, New South Wales, Australia.
² School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Kensington, Sydney, New South Wales, Australia.
³ Immune Biotherapies Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
⁴ VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
⁵ Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, Sydney, New South Wales, Australia.
⁶ Data Science Platform, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
⁷ Sydney Mass Spectrometry, University of Sydney, Sydney, New South Wales, Australia.
⁸ Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
⁹ Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia.
¹⁰ Department of Surgery, University of Melbourne, Melbourne, Australia.
¹¹ Royal North Shore Hospital, St Leonards, Sydney, New South Wales, Australia.
¹² Centre for Healthy Ageing, Centenary Institute, Sydney, New South Wales, Australia.
¹³ School of Sport, Exercise and Rehabilitation Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
¹⁴ St. Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
¹⁵ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW), Kensington, Sydney, New South Wales, Australia.
¹⁶ QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
¹⁷ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁸ School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia.
¹⁹ Department of Bioengineering & Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
²⁰ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
²¹ Department of Medical Oncology and Illawarra Shoalhaven Local Health District, Wollongong, New South Wales, Australia.
²² Cancer Research UK Scotland Institute, Glasgow, UK.
²³ School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK.
²⁴ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

Abstract

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^R172HC 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^R172HC 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.

MeSH terms

Animals
Arginine / analogs & derivatives
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
Signal Transduction* / drug effects
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism

Substances

Receptors, Neuropeptide Y
Neuropeptide Y
Tumor Suppressor Protein p53
neuropeptide Y-Y1 receptor
BIBO 3304
Npy1r protein, mouse
Arginine