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

Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visua...

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Veröffentlicht in:	Science advances Jg. 7; H. 40; S. eabh0363
Hauptverfasser:	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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Association for the Advancement of Science (AAAS) 01.10.2021 American Association for the Advancement of Science
Schlagworte:	Biomedicine and Life Sciences Cancer Cell Biology Computer Science Medical Imaging SciAdv r-articles
ISSN:	2375-2548, 2375-2548
Online-Zugang:	Volltext
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Zusammenfassung:	Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer. 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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC8480933 These authors contributed equally to this work.
ISSN:	2375-2548 2375-2548
DOI:	10.1126/sciadv.abh0363