Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status.
Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status.
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DOI：
10.1126/sciadv.abh0363
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发表时间：
2021-10
期刊：
影响因子：
13.6
通讯作者：
Timpson P
中科院分区：
文献类型：
--
作者：
Murphy KJ;Reed DA;Vennin C;Conway JRW;Nobis M;Yin JX;Chambers CR;Pereira BA;Lee V;Filipe EC;Trpceski M;Ritchie S;Lucas MC;Warren SC;Skhinas JN;Magenau A;Metcalf XL;Stoehr J;Major G;Parkin A;Bidanel R;Lyons RJ;Zaratzian A;Tayao M;Da Silva A;Abdulkhalek L;Australian Pancreatic Genome Initiative (APGI);Australian Pancreatic Cancer Matrix Atlas (APMA);Gill AJ;Johns AL;Biankin AV;Samra J;Grimmond SM;Chou A;Goetz JG;Samuel MS;Lyons JG;Burgess A;Caldon CE;Horvath LG;Daly RJ;Gadegaard N;Wang Y;Sansom OJ;Morton JP;Cox TR;Pajic M;Herrmann D;Timpson P
活体成像引导个体化医学方法以靶向胰腺癌的机械恢复性。胰腺导管腺癌（PDAC）是一种高转移性、化疗耐药的恶性肿瘤，其特征是致密的促结缔组织增生基质可调节PDAC的进展。在这里，我们可视化的瞬时操纵粘着斑激酶（FAK），它集成了双向细胞环境信号，使用活体荧光寿命成像显微镜的FAK为基础的Förster共振能量转移生物传感器在小鼠和患者衍生的PDAC模型。FUCCI细胞周期报告基因的平行实时定量指导我们改善PDAC对初级和次级部位标准治疗化疗的反应。重要的是，微图案化柱板和刚度可调矩阵用于查明环境线索对化学增敏的贡献，而流体流动诱导的剪切应力评估，患者来源的矩阵和个性化的体内模型使我们能够解构FAK抑制如何减少PDAC扩散。最后，通过Merlin状态对PDAC患者样本进行分层，发现预后不良的患者亚组可能在化疗前对FAK引发有反应。
Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer. 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.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
24.5
作者：
Chou A;Froio D;Nagrial AM;Parkin A;Murphy KJ;Chin VT;Wohl D;Steinmann A;Stark R;Drury A;Walters SN;Vennin C;Burgess A;Pinese M;Chantrill LA;Cowley MJ;Molloy TJ;Australian Pancreatic Cancer Genome Initiative (APGI);Waddell N;Johns A;Grimmond SM;Chang DK;Biankin AV;Sansom OJ;Morton JP;Grey ST;Cox TR;Turchini J;Samra J;Clarke SJ;Timpson P;Gill AJ;Pajic M
通讯作者：
Pajic M
影响因子：
21.3
作者：
Boyle, Sarah Theresa;Poltavets, Valentina;Samuel, Michael Susithiran
通讯作者：
Samuel, Michael Susithiran
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
3.7
作者：
Barnes, J. Matthew;Nauseef, Jones T.;Henry, Michael D.
通讯作者：
Henry, Michael D.