Journal
SCIENCE ADVANCES
Volume 7, Issue 40, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh0363
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Funding
- National Health and Medical Research Council (NHMRC)
- Australian Research Council (ARC)
- Cancer Council NSW
- Cancer Institute NSW (CINSW)
- Cancer Australia
- Tour de Cure
- St. Vincent's Clinic Foundation
- Suttons
- Sydney Catalyst (the Translational Cancer Research Centre of Central Sydney and Regional New South Wales)
- Avner Pancreatic Cancer Foundation Grant
- Len Ainsworth Fellowship in Pancreatic Cancer Research
- CINSW Early Career Research Fellowships
- Baxter Family Scholarships
- Philip Hemstritch Pancreatic Cancer Fellowships
- NHMRC
- Australian National Health and Medical Research Council
- Australian National Breast Cancer Foundation
- Susan G. Komen
- Cancer Research UK [A17196, A21139, A29996]
- European Research Council [FAKIR 648892]
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In this study, transient manipulation of focal adhesion kinase in PDAC was visualized using intravital fluorescence imaging, with real-time quantification of cell cycle reporter to improve chemotherapy response. Analysis of different matrices and environmental cues helped to reduce PDAC metastasis.
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.
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