Poster Presentation 38th Lorne Cancer Conference 2026

Deciphering netrin-1 implication in pancreatic cancer (#119)

Nicolas Braissand 1 2 3 , Hue Mai La 1 2 , Paul Nguyen 1 2 , Danni Upton 4 5 , Marina Pajic 4 6 , Tracy Putoczki 7 8 9 , Benjamin Ducarouge 10 , Patrick Mehlen 3 10 , Agnès Bernet 3 10 , Frederic Hollande 1 2 , Sean Grimmond 2
  1. Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
  2. Collaborative Centre for Genomic Cancer Medicine, University of Melbourne, Melbourne, VIC, Australia
  3. Laboratory Apoptosis, Cancer and Development, Centre de Recherche en Cancérologie de Lyon CRCL, Lyon, France
  4. School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia
  5. Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia
  6. Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, Sydney, New South Wales, Australia
  7. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  8. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
  9. Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
  10. NETRIS Pharma, Lyon, France

Netrin-1 (NTN-1) is a laminin-related protein initially identified for its role in axon guidance during development. However, it is now established that this protein is involved in other various cellular processes when bound to its receptors by triggering an intracellular signaling. Importantly, while NTN-1 is almost completely lost in healthy adult tissues, it is overexpressed in multiple tumor indications, interacting with dependence receptors such as DCC, Neogenin-1 and the UNC5 family to promote cell survival, epithelial-to-mesenchymal transition and to escape apoptosis. Based on these findings, a NTN-1 neutralising antibody (NP137) has been designed to block NTN-1 signaling and its cancer-promoting features, showing promising therapeutic effect in preclinical models and several clinical trials.

Our study investigated the role of NTN-1 in pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies with high resistance to chemotherapy and increasing incidence rate, as it is expected to become the 2nd leading cause of cancer-related deaths by 2030.

Bioinformatic analyses demonstrated that NTN-1 and its receptors are expressed by several cell types (tumour cells, cancer-associated fibroblasts, intrapancreatic neurons) in human PDAC samples and showed increased expression in tumour cells upon chemotherapy treatment, indicating a potential interest for treatment combination with NP137. Using PDAC-derived organoids and in vivo mouse models, we investigated NTN-1 expression and identified a significant effect of NP137 treatment on tumour growth when combined with Folfirinox chemotherapy, that was not detected with NP137 or chemotherapy alone. To unravel the mechanisms of action of NP137 in PDAC, tumours were collected and analysed for apoptosis and proliferation markers, as well as immune infiltration and tissue stiffness.

Additionally, spatial transcriptomic analyses of PDAC patients allowed us to highlight NTN-1 presence near nerve bundles that infiltrate tumours, potentially indicating an impact of NTN-1 in tumour innervation, as its initial role of axon guidance suggests. These findings are currently investigated in the treated mouse samples described above and could also partially explain NP137 mode of action.

Altogether, this study investigated the role and the biological effects of NTN-1 in PDAC and identified it as an interesting target to overcome chemotherapy resistance and improve patient outcomes.