Poster Presentation Hunter Cell Biology Meeting 2025

Targeting the NPY/NPY1R signaling axis impairs metastasis and tissue wasting in pancreatic cancer (#116)

Cecilia R Chambers 1 2 , Supitchaya Watakul 1 2 , 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 3 , Xanthe Metcalf 1 , Shona Ritchie 1 2 , Antonia Cadell 1 2 , Janett Stoehr 1 , Astrid Magenau 1 2 , Diego Chacon-Fajardo 1 , 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 4 , Alexander Rookyard 4 , Angela Connolly 4 , Ben Crossett 4 , Yen TH Tran 5 , Peter Kaltzis 5 , Claire Vennin 1 2 , Marija Dinevska 1 6 7 , Australian Pancreatic Cancer Genome Initiative (APGI) 1 , Australian Pancreatic Cancer Matrix Atlas (APMA) 1 , David R Croucher 1 2 , Jaswinder Samra 8 , Anubhav Mittal 8 , Robert J Weatheritt 1 , Andrew Philp 9 10 , Gonzalo Del Monte-Nieto 5 , Lei Zhang 2 11 , Ronaldo F Enriquez 1 , Thomas R Cox 1 2 , Yan-Chuan C Shi 1 2 , Mark Pinese 2 12 , Nicola Waddell 13 , Hao-Wen Sim 1 2 14 , Tatyana Chtanova 1 15 , Yingxiao Wang 16 17 , Anthony M Joshua 1 2 , Lorraine Chantrill 18 , Thomas RJ Evans 19 20 , Anthony J Gill 1 8 21 , Jennifer P Morton 19 20 , Marina Pajic 1 2 , Daniel Christ 1 2 22 , Herbert Herzog 2 11 22 , Paul Timpson 1 2 22 , David Herrmann 1 2 22
  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. VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
  4. Sydney Mass Spectrometry, The University of Sydney, Sydney, NSW, Australia
  5. The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  6. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia
  7. Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
  8. Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia
  9. Centre for Healthy Ageing, Centenary Institute, Sydney, NSW, Australia
  10. School of Sport, Exercise and Rehabilitation Sciences, University of Technology Sydney, Sydney, NSW, Australia
  11. St Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney, NSW, Australia
  12. Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW), Kensington, Sydney, NSW, Australia
  13. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  14. NHMRC Clinical trials Centre, University of Sydney, Sydney, NSW, Australia
  15. School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales (UNSW), Sydney, NSW, Australia
  16. Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA
  17. Alfred E. Mann Department of Biomedical Engineering , University of Southern California, Los Angeles, California, United States
  18. Department of Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, NSW, Australia
  19. Cancer Research UK Scotland Institute, Glasgow, United Kingdom
  20. School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
  21. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  22. #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 homeostasis1,2, has also been shown to promote tumorigenesis in a range of cancer types3,4, 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 immunohistochemistry5. 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 liver5. 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 wasting6.

Transcriptomic and proteomic assessment via RNA-seq and mass spectrometry proteomics, respectively, identified ~500 differentially expressed transcripts and proteins in pancreatic tumours following Npy1r knockout5. While some of these differentially expressed transcripts/proteins have already been shown to have a role in cancer progression and metastasis, 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 model5. 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 vivo5. Immunohistochemical analysis revealed a significant reduction in cell proliferation5, suggesting that NPY1R inhibition reduces metastasis by decreasing metastatic growth.

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.

  1. Zhu, Y et al., Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat. Nature 634, 243–250 (2024).
  2. Yan, C et al., Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity. Nature Communications, 12, 2622 (2021).
  3. Dietrich, P et al., Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer. The Journal of Clinical Investigation, 130: 2509–2526 (2020).
  4. Cheng, Y et al., Depression-Induced Neuropeptide Y Secretion Promotes Prostate Cancer Growth by Recruiting Myeloid Cells. Clinical Cancer Research 25: 2621-2632 (2019).
  5. Chambers, CR et al., Targeting the NPY/NPY1R Signaling Axis in Mutant p53-Dependent Pancreatic Cancer Impairs Metastasis. Science Advances, 2025 in press.
  6. Danai, LV et al., Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature, 558, 600-604 (2018).