In-person Oral Presentation 34th Lorne Cancer Conference 2022

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status (#29)

Kendelle J Murphy 1 2 , Daniel A Reed 1 2 , Claire Vennin 1 2 , James RW Conway 1 2 , Max Nobis 1 2 , Julia X Yin 1 , Cecilia R Chambers 1 2 , Brooke R Pereira 1 2 , Elysse C Filipe 1 2 , Michael Trpceski 1 , Shona Ritchie 1 2 , Morghan C Lucas 1 , Sean C Warren 1 2 , Joanna N Skhinas 1 , Astrid Magenau 1 2 , Xanthe L Metcalf 1 , Janett Stoehr 1 , Gretal Major 1 , Ashleigh Parkin 1 2 , Romain Bidanel 1 , Ruth J Lyons 1 , Anaiis Zaratzian 1 , Michael Tayao 1 , Andrew Da Silva 1 , Lea Abdulkhalek 1 , Australian Pancreatic Cancer Genome Initiative (APGI) 1 , Australian Pancreatic Cancer Matrix Atlas (APMA) 1 , Anthony J Gill 1 , Amber L Johns 1 , Andrew V Biankin 3 , Jaswinder Samra 4 , Sean M Grimmond 5 , Angela Chou 1 , Jacky G Goetz 6 , Michael S Samuel 7 , J Guy Lyons 8 , Andrew Burgess 9 , C Elizabeth Caldon 1 2 , Lisa G Horvath 1 , Roger J Daly 10 , Nikolaj Gadegaard 11 , Yingxiano Wang 12 , Owen J Sansom 13 , Jennifer P Morton 13 , Thomas R Cox 1 2 , Marina Pajic 1 2 , David Herrmann 1 2 , 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 aggressive, metastatic and chemoresistant malignancy that is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualised transient manipulation or "priming" of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signalling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in both mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care gemcitabine/Abraxane chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues and stromal stiffness to chemosensitisation, 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. Last, stratification of PDAC patient samples via Merlin status revealed a subset of patients with a poor prognosis and that are likely to respond to FAK priming prior to chemotherapy.