The Pancreas Summit 2025

Targeting the NPY/NPY1R Signaling Axis Impairs Metastasis in Pancreatic Cancer (128230)

Cecilia R Chambers 1 2 , Supitchaya Watakul 1 , Peter Schofield 1 2 , Anna E Howell 1 , Jessie Zhu 1 2 , Alice MH Tran 1 , Nadia Kuepper 1 , Daniel A Reed 1 2 , Kendelle J Murphy 1 2 , Lily M Channon 1 , Brooke A Pereira 1 2 , Victoria M Tyma 1 , Victoria Lee 1 , Michael Trpceski 1 2 , Jake Henry 1 2 , Pauline Melenec 1 , Lea Abdulkhalek 1 , Max Nobis 1 2 , Xanthe Metcalf 1 , Shona Ritchie 1 2 , Antonia Cadell 1 2 , Janett Stoehr 1 , Astrid Magenau 1 2 , Diego Chacon-Fajardo 1 2 , Jessica L Chitty 1 2 , Savannah O'Connell 1 , Anaiis Zaratzian 1 , Michael Tayao 1 , Andrew Da Silva 1 , Ruth J Lyons 1 , Leonard D Goldstein 1 2 , Ashleigh Dale 3 , Alexander Rookyard 3 , Angela Connolly 3 , Ben Crossett 3 , Yen TH Tran 4 , Peter Kaltzis 4 , Claire Vennin 1 2 , Marija Dinevska 1 5 6 , David R Croucher 1 2 , Jaswinder Samra 7 , Anubhav Mittal 7 , Robert J Weatheritt 1 , Andrew Philp 8 9 , Gonzalo Del Monte-Nieto 4 , Lei Zhang 2 10 , Ronaldo F Enriquez 1 , Thomas R Cox 1 2 , Yan-Chuan Shi 1 2 , Mark Pinese 2 11 , Nicola Waddell 12 , Hao-Wen Sim 1 2 13 , Tatyana Chtanova 1 14 , Yingxiao Wang 15 16 , Anthomy M Joshua 1 2 , Lorraine Chantrill 17 , Thomas RJ Evans 18 19 , Anthony J Gill 1 7 20 , Jennifer P Morton 18 19 , Marina Pajic 1 2 , Daniel Christ 1 2 21 , Herbert Herzog 1 2 21 , Paul Timpson 1 2 21 , David Herrmann 1 2 21
  1. Garvan Institute / The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
  2. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Kensignton, Sydney, NSW, Australia
  3. Sydney Mass Spectrometry, The University of Sydney, Sydney, NSW, Australia
  4. The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  5. Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
  6. Department of Surgery, University of Melbourne, Melbourne, Australia
  7. Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia
  8. Centre for Healthy Ageing, Centenary Institute, Sydney, NSW, Australia
  9. School of Sport, Exercise and Rehabilitation Sciences, University of Technology Sydney, Sydney, NSW, Australia
  10. St Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney, NSW, Australia
  11. Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW), Kensington, Sydney, NSW, Australia
  12. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  13. NHMRC Clinical trials Centre, University of Sydney, Sydney, NSW, Australia
  14. School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales (UNSW), Sydney, NSW, Australia
  15. Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA
  16. Alfred E. Mann Department of Biomedical Engineering , University of Southern California, Los Angeles, California, United States
  17. Department of Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, NSW, Australia
  18. Cancer Research UK Scotland Institute, Glasgow, United Kingdom
  19. School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
  20. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  21. #equal contribution, co-senior author

Pancreatic Cancer (PC) is a highly metastatic malignancy. Over 80% of PC patients 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. 

Here, we show that expression of NPY and its receptor NPY1R are upregulated in mouse PC models and human PC patients via q-RT-PCR, chromogenic RNAscope and immunohistochemistry. Using the genetically engineered, autochthonous KPR172HC mouse model of highly metastatic PC (Pdx1-Cre; LSL-KrasG12D/+; Trp53R172H/+) we demonstrate that pancreas-specific and whole-body knockout of Npy1r significantly decreases metastasis to the liver. We also observed an increase in adipose and muscle tissue mass in Npy1r knockout settings, providing an additional benefit on top of reducing metastasis in PC, since PC progression is often associated with tissue wasting.

RNA-seq and mass spectrometry proteomics identified ~500 differentially expressed transcripts and proteins in pancreatic tumours following Npy1r knockout, of which many are underexplored in PC warranting further studies based on our datasets.

Complementing our genetic studies, we identify that treatment with the selective NPY1R antagonist BIBO3304 significantly reduces KPR172HC migratory capacity on fibroblast-derived 2.5D cell-derived matrices, which could, in part, be contributing to the anti-metastatic effect observed upon Npy1r knockout in the KPR172HC mouse model. Importantly, pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing metastasis in the liver in vivo.

Together, our results reveal that NPY/NPY1R signaling is a novel anti-metastatic target in PC. Targeting this pathway may represent a highly effective anti-metastatic strategy for future assessment in conjunction with standard-of-care approaches to improve outcomes for PC patients.