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
Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia.
St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia.
Sci Adv. 2021 Oct;7(40):eabh0363. doi: 10.1126/sciadv.abh0363. Epub 2021 Sep 29.
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.
胰腺导管腺癌（PDAC）是一种具有高度转移性、化疗耐药性的恶性肿瘤，其特征是存在密集的促结缔组织增生性基质，该基质可调节PDAC的进展。在此，我们利用基于黏着斑激酶（FAK）的Förster共振能量转移生物传感器，在小鼠和患者来源的PDAC模型中进行活体荧光寿命成像显微镜观察，实现了对整合双向细胞-环境信号的FAK的瞬时操控。FUCCI细胞周期报告基因的并行实时定量分析指导我们改善了PDAC在原发和继发部位对标准护理化疗的反应。至关重要的是，微图案化柱板和刚度可调基质被用于确定环境线索对化学增敏作用的贡献，而流体流动诱导的剪切应力评估、患者来源的基质和个性化体内模型使我们能够解析FAK抑制如何减少PDAC的扩散。最后，通过Merlin状态对PDAC患者样本进行分层，发现了一个预后较差的患者亚组，他们可能在化疗前对FAK启动治疗有反应。
