Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status
Kendelle J. Murphy
(1, 2)
,
Daniel A. Reed
(1, 2)
,
Claire Vennin
(1, 2, 3)
,
James R. W. Conway
(1, 2, 4)
,
Max Nobis
(1, 2)
,
Julia X. Yin
(1, 2)
,
Cecilia R. Chambers
(1, 2)
,
Brooke A. Pereira
(1, 2)
,
Victoria Lee
(1)
,
Elysse C. Filipe
(1, 2)
,
Michael Trpceski
(1)
,
Shona Ritchie
(1, 2)
,
Morghan C. Lucas
(1, 2)
,
Sean C. Warren
(1, 2)
,
Joanna N. Skhinas
(1)
,
Astrid Magenau
(1, 2)
,
Xanthe L. Metcalf
(1)
,
Janett Stoehr
(1)
,
Gretel Major
(1)
,
Ashleigh Parkin
(1, 2)
,
Romain Bidanel
(1)
,
Ruth J. Lyons
(1)
,
Anaiis Zaratzian
(1)
,
Michael Tayao
(1)
,
Andrew da Silva
(1)
,
Lea Abdulkhalek
(1)
,
Anthony J. Gill
(1, 2, 5, 6)
,
Amber L. Johns
(1)
,
Andrew V. Biankin
(7, 8)
,
Jaswinder Samra
(6)
,
Sean M. Grimmond
(9)
,
Angela Chou
(1, 5, 6)
,
Jacky Goetz
(10, 11)
,
Michael S. Samuel
(12, 13)
,
J. Guy Lyons
(5, 14)
,
Andrew Burgess
(15, 5)
,
C. Elizabeth Caldon
(1, 2)
,
Lisa G. Horvath
(1, 2, 5)
,
Roger J. Daly
(16)
,
Nikolaj Gadegaard
(7)
,
Yingxiao Wang
(17)
,
Owen J. Sansom
(7, 18)
,
Jennifer P. Morton
(7, 18)
,
Thomas R. Cox
(1, 2)
,
Marina Pajic
(1, 2)
,
David Herrmann
(1, 2)
,
Paul Timpson
(1, 2)
1
Garvan Institute of medical research
2 UNSW - University of New South Wales [Sydney]
3 NKI - Netherlands Cancer Institute
4 University of Turku
5 The University of Sydney
6 RNSH - Royal North Shore Hospital
7 University of Glasgow
8 Glasgow Royal Infirmary
9 V3C - Victorian Comprehensive Cancer Centre [Melbourne, Australia]
10 IRM - Immuno-Rhumatologie Moléculaire
11 FMTS - Fédération de Médecine Translationnelle de Strasbourg
12 University of South Australia [Adelaide]
13 University of Adelaide
14 RPAH - Royal Prince Alfred Hospital [Camperdown, Australia]
15 Anzac Research Institute
16 Monash University [Melbourne]
17 UC San Diego - University of California [San Diego]
18 Cancer Research UK Beatson Institute [Glasgow]
2 UNSW - University of New South Wales [Sydney]
3 NKI - Netherlands Cancer Institute
4 University of Turku
5 The University of Sydney
6 RNSH - Royal North Shore Hospital
7 University of Glasgow
8 Glasgow Royal Infirmary
9 V3C - Victorian Comprehensive Cancer Centre [Melbourne, Australia]
10 IRM - Immuno-Rhumatologie Moléculaire
11 FMTS - Fédération de Médecine Translationnelle de Strasbourg
12 University of South Australia [Adelaide]
13 University of Adelaide
14 RPAH - Royal Prince Alfred Hospital [Camperdown, Australia]
15 Anzac Research Institute
16 Monash University [Melbourne]
17 UC San Diego - University of California [San Diego]
18 Cancer Research UK Beatson Institute [Glasgow]
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.
Domaines
Imagerie médicaleOrigine | Fichiers produits par l'(les) auteur(s) |
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