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

Murphy, K. J. et al. (2021) Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status. Science Advances, 7(40), eabh0363. (doi: 10.1126/sciadv.abh0363) (PMID:34586840) (PMCID:PMC8480933)

Abstract

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 Förster 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, micropatterned 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Grimmond, Professor Sean and Biankin, Professor Andrew and Gadegaard, Professor Nikolaj and Sansom, Professor Owen
• Authors: Murphy, K. J., Reed, D. A., Vennin, C., Conway, J. R. W., Nobis, M., Yin, J. X., Chambers, C. R., Pereira, B. A., Lee, V., Filipe, E. C., Trpceski, M., Ritchie, S., Lucas, M. C., Warren, S. C., Skhinas, J. N., Magenau, A., Metcalf, X. L., Stoehr, J., Major, G., Parkin, A., Bidanel, R., Lyons, R. J., Zaratzian, A., Tayao, M., Da Silva, A., Abdulkhalek, L., Gill, A. J., Johns, A. L., Biankin, A. V., Samra, J., Grimmond, S. M., Chou, A., Goetz, J. G., Samuel, M. S., Lyons, J. G., Burgess, A., Caldon, C. E., Horvath, L. G., Daly, R. J., Gadegaard, N., Wang, Y., Sansom, O. J., Morton, J. P., Cox, T. R., Pajic, M., Herrmann, D., and Timpson, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Science and Engineering > School of Engineering > Biomedical Engineering
• Journal Name: Science Advances
• Publisher: American Association for the Advancement of Science
• ISSN: 2375-2548
• ISSN (Online): 2375-2548
• Published Online: 29 September 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Science Advances 7(40): eabh0363
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172025		FAKIR: Focal Adhesion Kinetics In nanosurface Recognition	Nikolaj Gadegaard	European Research Council (ERC)	648892	ENG - Biomedical Engineering