Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status
: Murphy Kendelle J., Reed Daniel A., Vennin Claire, Conway James R. W., Nobis Max, Yin Julia X., Chambers Cecilia R., Pereira Brooke A., Lee Victoria, Filipe Elysse C., Trpceski Michael, Ritchie Shona, Lucas Morghan C., Warren Sean C., Skhinas Joanna N., Magenau Astrid, Metcalf Xanthe L., Stoehr Janett, Major Gretel, Parkin Ashleigh, Bidanel Romain, Lyons Ruth J., Zaratzian Anaiis, Tayao Michael, Da Silva Andrew, Abdulkhalek Lea, Gill Anthony J., Johns Amber L., Biankin Andrew V, Samra Jaswinder, Grimmond Sean M., Chou Angela, Goetz Jacky G., Samuel Michael S., Lyons J. Guy, Burgess Andrew, Caldon C. Elizabeth, Horvath Lisa G., Daly Roger J., Gadegaard Nikolaj, Wang Yingxiao, Sansom Owen J., Morton Jennifer P., Cox Thomas R., Pajic Marina, Herrmann David, Timpson Paul
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
: 2021
: Science Advances
: SCIENCE ADVANCES
: SCI ADV
: ARTN eabh0363
: 7
: 40
: 27
: 2375-2548
: 2375-2548
DOI: https://doi.org/10.1126/sciadv.abh0363
: https://www.science.org/doi/10.1126/sciadv.abh0363
: https://research.utu.fi/converis/portal/detail/Publication/67694057
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Forster resonance energy transfer biosensor in 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 chemotherapy at primary and secondary sites. Critically, micro-patterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, 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 patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy.
