Poster Presentation 38th Lorne Cancer Conference 2026

Targeting the NPY/NPY1R signaling axis impairs metastasis and tissue wasting in pancreatic cancer (#159)

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 2 , Victoria Lee 1 , Michael Trpceski 1 2 , Lei Zhang 2 3 , Anthony J Gill 1 4 5 , Jennifer P Morton 6 7 , Marina Pajic 1 2 , Daniel Christ 1 2 8 , Herbert Herzog 2 3 8 , Paul Timpson 1 2 8 , David Herrmann 1 2 8
  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. St Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney, NSW, Australia
  4. Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia
  5. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  6. Cancer Research UK Scotland Institute, Glasgow, United Kingdom
  7. School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
  8. #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 immunohistochemistry. Using the genetically engineered, autochthonous KPC 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 wasting5.

Transcriptomic and proteomic assessment via RNA-seq and mass spectrometry proteomics, respectively, identified ~500 differentially expressed transcripts and proteins in pancreatic tumours following Npy1r knockout. 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 KPC 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 KPC 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. Immunohistochemical analysis revealed a significant reduction in cell proliferation, 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 outcome 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-specifc 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. Danai, LV et al., Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature, 558, 600-604 (2018).