Oral Presentation 35th Lorne Cancer Conference 2023

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine (#3)

Kendelle J Murphy 1 2 , Daniel A Reed 1 2 , Cecilia R Chambers 1 2 , Claire Vennin 1 2 , James R Conway 1 2 , Max Nobis 1 2 , Julia X Yin 1 2 , Brooke A Pereira 1 2 , Victoria Lee 1 , Elysse C Filipe 1 2 , Michael Trpceski 1 2 , Shona Ritchie 1 2 , Morghan C Lucas 1 2 , Sean C Warren 1 2 , Joanna N Skhinas 1 , Astrid Magenau 1 , Xanthe L Metcalf 1 , Janett Stoehr 1 , Gretal Major 1 , Ashleigh Parkin 1 2 , Romain Bidanel 1 , Ruth J Lyons 1 , Lily Channon 1 , Anna Howell 1 , Anaiis Zaratzian 1 , Michael Tayao 1 , Andrew Da Silva 1 , Lea Adbulkhalek 1 , Anthony J Gill 1 2 , Amber L Johns 1 , Andrew V Biankin 3 , Jaswinder Samra 4 , Sean Grimmond 5 , Angela Chou 1 2 , Jacky G Goetz 6 , Michael S Samuel 7 , J Guy Lyons 8 , Andrew Burgess 9 , C Elizabeth Caldon 1 2 , Lisa G Horvath 1 2 , Roger J Daly 10 , Nikolaj Gadegaard 11 , Yingxiao Wang 12 , Owen J Sansom 13 , Jennifer P Morton 13 , Thomas R Cox 1 , Marina Pajic 1 2 , David Herrmann 1 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, Sydney, NEW SOUTH WALES, Australia
  2. St Vincents Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW, Australia
  3. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  4. Department of Surgery, Royal North Shore Hospital, Sydney, NSW, Australia
  5. University of Melbourne Center for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
  6. INSERM UMR, Tumour Biomechanics, Université de Strasbourg, Strasbourg, France
  7. Center for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia
  8. Dermatology, Sydney Medical School, University of Sydney, Camperdown, NSW, Australia
  9. ANZAC Research Institute , Sydney, NSW, Australia
  10. Monash Biomedicine Discovery Institute, Monash University , Melbourne, VIC, Australia
  11. James Watt School of Engineering, University of Glasgow, Glasgow, UK
  12. Institute of Engineering in Medicine, University of California, San Diego, CA, USA
  13. Cancer Research UK, Beatson Institute, Glasgow, UK

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemo-resistant malignancy and is characterized by a dense, desmoplastic stroma that increases the biomechanical force load on cancer cells and is thought to both promote and restrict disease advancement. Using the p53 mutant KPC mouse model of PDAC, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signalling. We used the fluorescent ubiquitination-based cell cycle indicator (FUCCI) cell cycle reporter for in vivo imaging to monitor dynamic changes in FAK activity, stromal biomechanics and gemcitabine/Abraxane-induced effects. Critically, micropatterned pillar plates and stiffness-tuneable matrices were used to pinpoint the contribution of mechanical environmental cues to chemo-sensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. In a prevision medicine approach, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy. This dataset has led to the establishment of a Phase II clinical trial of first-line FAK inhibition in combination with Gemcitabine/Abraxane in PDAC Patients (NCT05355298).