Poster Presentation 38th Lorne Cancer Conference 2026

Pancreatic cancer secretome reveals PCSK9 as a co-target to sensitise tumours to chemotherapy and reduce metastasis (#244)

Shona Ritchie 1 2 , Victoria Tyma 1 2 , Shanna Hafiz 2 , Cecilia Chambers 1 2 , Kendelle Murphy 1 2 , Astrid Magenau 1 2 , Katie Gordon 1 2 , Victoria Lee 1 2 , Ying Fei Liew 1 2 , Anna Howell 1 2 , Alice Tran 2 3 , Nadia Kuepper 1 2 , Vrinda Johri 1 2 , Daniel Reed 2 , Zoe Phan 1 2 , Sarah Alexandrou 1 2 , Deborah Barkauskas 1 2 , Angela Fontain-Titley 1 2 , Luke O'Regan 1 2 , Sai Prasad Chitti 4 , Ruth Lyons 1 2 , Anaiis Zaratizan 1 2 , Michael Tayao 1 2 , Andrew Da Silva 1 2 , Julia Yin 2 , Xiao Qian Wang 1 2 , Leonard Goldstein 1 2 , Xufeng Lin 1 2 , Sharissa Latham 1 2 , Australian Pancreatic Cancer Genome Initiative (APGI) 2 , Australian Pancreatic Cancer Matrix Atlas (APMA) 2 , David Croucher 1 2 , Thomas Cox 1 2 , Lorraine Chantrill 2 , Anthony Joshua 2 , Thomas Jeffry Evans 5 , Anthony Gill 2 6 , Jasminder Samra 6 , Susan Clark 1 2 , Lisa Horvath 2 7 , Jennifer Morton 5 8 , Suresh Mathivanan 4 , Max Nobis 2 9 , C. Elizabeth Caldon 1 2 , Marina Pajic 1 2 , Ruth Pidsley 1 2 , David Herrmann 1 2 , Brooke Pereira 1 2 , Paul Timpson 1 2
  1. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  2. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  4. Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia
  5. Cancer Research UK Beatson Institute, Glasgow, Scotland, UK
  6. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  7. Chris O’Brien Lifehouse, Sydney, NSW, Australia
  8. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
  9. Intravital Imaging Expertise Center, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) exhibit a limited response to standard-of-care chemotherapy. The cancer secretome may offer novel therapeutic targets to enhance current treatments. 

Objective: Through multi-modal profiling of PDAC cells, we aimed to identify secreted proteins contributing to PDAC progression and metastasis, to reveal new candidates for co-targeting with standard-of-care chemotherapy.

Design: RNA sequencing (RNAseq) and mass spectrometry (MS)-based proteomics assessed the transcriptome, secretome and exosome profile of PDAC cells from the highly-metastatic KPC and the poorly-metastatic KPflC genetically engineered mouse models (GEMMs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) was identified as a potential co-target and was subsequently validated in PDAC patient cohorts. PCSK9 inhibition was evaluated in combination with standard-of-care gemcitabine/nab-paclitaxel (GnP) chemotherapy using in vitro and in vivo models of PDAC. Therapy response was visualised via multiphoton imaging of the fluorescent ubiquitination-based cell cycle indicator (FUCCI) reporter.  

Results: PCSK9 expression and secretion was enhanced in highly-metastatic PDAC cells. High PCSK9 expression was associated with increased histopathological tumour grade and worse survival in PDAC patients. PCSK9 inhibition impeded cancer cell invasion, reduced tumour growth in vivo, and further sensitised cells to GnP. RNAseq revealed a dysregulation of cell cycle-associated genes, confirmed by FUCCI multiphoton microscopy. In vitro experiments and in vivo models of metastasis revealed that PCSK9 inhibition combined with GnP significantly reduced cancer cell survival and liver metastasis.  

Conclusion: This study highlights an anti-cancer role for PCSK9 inhibition in combination with GnP chemotherapy for pancreatic cancer.