Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
entrez:
29
9
2021
pubmed:
30
9
2021
medline:
30
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34586840
doi: 10.1126/sciadv.abh0363
pmc: PMC8480933
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eabh0363Subventions
Organisme : NIBIB NIH HHS
ID : R01 EB029122
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM140929
Pays : United States
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