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Author Spotlight: Revolutionizing Pancreatic Disease Understanding Through Advanced Intravital Imaging
Published on: October 6, 2023
Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin
Kendelle J Murphy1,2, Daniel A Reed1,2, Claire Vennin1,2,3
1Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia.
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.
Insights
Focal adhesion kinase (FAK) inhibition can improve pancreatic cancer (PDAC) chemotherapy response and reduce metastasis. Targeting FAK, especially in Merlin-negative patients, offers a promising strategy for treating this aggressive cancer.
Area of Science:
- Oncology
- Cell Biology
- Biophysics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer known for metastasis and resistance to chemotherapy.
- The tumor microenvironment, particularly the desmoplastic stroma, significantly influences PDAC progression.
- Focal adhesion kinase (FAK) plays a crucial role in cell-environment signaling, impacting cancer behavior.
Purpose of the Study:
- To visualize and understand FAK signaling dynamics in PDAC using advanced imaging techniques.
- To identify strategies for improving PDAC response to chemotherapy by modulating FAK and environmental factors.
- To investigate the mechanisms by which FAK inhibition reduces PDAC metastasis.
Main Methods:
- Intravital Förster resonance energy transfer (FRET) biosensor imaging of FAK in mouse and patient-derived PDAC models.
- Real-time cell cycle monitoring using FUCCI reporters.
- Micropatterned substrates and stiffness-tunable matrices to assess environmental cues.
- Shear stress assessment, patient-derived matrices, and personalized in vivo models.
Main Results:
- Transient FAK manipulation was visualized, correlating with PDAC progression.
- Chemotherapy response was improved by integrating FAK signaling insights with cell cycle reporters.
- Environmental factors like matrix stiffness and shear stress were shown to influence chemosensitization and metastasis.
- FAK inhibition was demonstrated to reduce PDAC spread in personalized models.
Conclusions:
- FAK inhibition is a viable strategy to enhance chemotherapy efficacy and reduce metastasis in PDAC.
- Environmental cues significantly contribute to chemosensitization and can be leveraged for therapeutic benefit.
- Stratification of PDAC patients by Merlin status identified a subset likely to benefit from FAK inhibition prior to chemotherapy.
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