Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

被引：209

作者：

Chin, Venessa T. ^{[1
,2
]}

Vennin, Claire ^{[1
,2
]}

Warren, Sean C. ^{[1
,2
]}

Lucas, Morghan C. ^{[1
,2
]}

Herrmann, David ^{[1
,2
]}

Magenau, Astrid ^{[1
,2
]}

Melenec, Pauline ^{[1
,2
]}

Walters, Stacey N. ^{[1
,2
]}

Monte-Nieto, Gonzalo dl ^{[2
,3
]}

Conway, James R. W. ^{[1
,2
]}

Nobis, Max ^{[1
,2
]}

Allam, Amr H. ^{[1
,2
]}

McCloy, Rachael A. ^{[1
,2
]}

Currey, Nicola ^{[1
,2
]}

Pinese, Mark ^{[1
,2
]}

Boulghourjian, Alice ^{[1
]}

Zaratzian, Anaiis ^{[1
]}

Adam, Arne A. S. ^{[3
]}

Heu, Celine ^{[4
]}

Nagrial, Adnan M. ^{[1
]}

Chou, Angela ^{[1
,2
,5
]}

Steinmann, Angela ^{[1
]}

Drury, Alison ^{[1
]}

Froio, Danielle ^{[1
]}

Giry-Laterriere, Marc ^{[1
,2
]}

Harris, Nathanial L. E. ^{[1
,6
]}

Phan, Tri ^{[1
,2
]}

Jain, Rohit ^{[7
,8
]}

Weninger, Wolfgang ^{[7
,8
,9
]}

McGhee, Ewan J. ^{[10
]}

Whan, Renee ^{[3
]}

Johns, Amber L. ^{[1
,11
,12
,13
]}

Samra, Jaswinder S. ^{[10
,13
,14
]}

Chantrill, Lorraine ^{[1
,13
,14
]}

Gill, Anthony J. ^{[1
,11
,12
,13
,15
]}

Kohonen-Corish, Maija ^{[1
,2
,16
]}

Harvey, Richard P. ^{[2
,3
,17
]}

Biankin, Andrew V. ^{[13
,18
,19
]}

Evans, T. R. Jeffry ^{[10
]}

Anderson, Kurt I. ^{[10
]}

Grey, Shane T. ^{[1
,12
]}

Ormandy, Christopher J. ^{[1
,12
]}

Gallego-Ortega, David ^{[1
,12
]}

Wang, Yingxiao ^{[20
]}

Samuel, Michael S. ^{[21
,22
]}

Sansom, Owen J. ^{[10
]}

Burgess, Andrew ^{[1
,2
]}

Cox, Thomas R. ^{[1
,2
]}

Morton, Jennifer P. ^{[10
]}

Pajic, Marina ^{[1
,2
]}

机构：

[1] Garvan Inst Med Res, Kinghorn Canc Ctr, 370 Victoria St, Sydney, NSW, Australia

[2] Univ Melbourne, Victorian Comprehens Canc Ctr, Ctr Canc Re, 305 Grattan St, Melbourne, Vic 3000, Australia

[3] Univ Verona, ARC NET Ctr Appl Res Canc, Via Artigliere 19, I-37129 Verona, Provience Veron, Italy

[4] St Vincents Hosp, 390 Victoria St, Darlinghurst, NSW 2010, Australia

[5] Queensland Inst Med Res, Berghofer Med Res Inst, 300 Herston Rd, Herston, Qld 4006, Australia

[6] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia

[7] Royal North Shore Hosp, Westbourne St, St Leonards, NSW 2065, Australia

[8] Bankstown Hosp, Eldridge Rd, Bankstown, NSW 2200, Australia

[9] Liverpool Hosp, Elizabeth St, Liverpool, Merseyside 2170, Australia

[10] Westmead Hosp, Hawkesbury & Darcy Rd, Westmead, NSW 2145, Australia

[11] Royal Prince Alfred Hosp, Missenden Rd, Camperdown, NSW 2050, Australia

[12] Prince Wales Hosp, Barker St, Randwick, NSW 2031, Australia

[13] Fremantle Hosp, Alma St, Fremantle, WA 6959, Australia

[14] Sir Charles Gairdner Hosp, Hosp Ave, Nedlands, WA 6008, Australia

[15] St John God Healthcare, 12 Salvado Rd, Subiaco, WA 6008, Australia

[16] Royal Adelaide Hosp, Adelaide, SA 5000, Australia

[17] Flinders Med Ctr, Flinders Dr, Bedford Pk, Qld 5042, Australia

[18] Envoi Pathol, 1-49 Butterfield St, Herston, Qld 4006, Australia

[19] Princess Alexandra Hosp, Cornwall St,Ipswich Rd, Brisbane, Qld 4102, Australia

[20] Austin Hosp, 145 Studley Rd, Heidelberg, Vic 3084, Australia

[21] Johns Hopkins Med Inst, 600 North Wolfe St, Baltimore, MD 21287 USA

[22] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 384期

基金：

澳大利亚研究理事会; 英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

DUCTAL ADENOCARCINOMA; CELL INVASION; EXTRACELLULAR-MATRIX; CLEAVAGE FURROW; RHO-KINASE/ROCK; TUMOR; ACTIVATION; REVEALS; TENSION; MIGRATION;

D O I：

10.1126/scitranslmed.aai8504

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Forster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

引用

页数：17

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