title: Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.
abstract: 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 Förster 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.
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Vennin
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Venessa T
authors.identifier: 0000-0002-4630-4451
authors.initials: VT
authors.lastname: Chin
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Sean C
authors.identifier: 0000-0002-5253-7147
authors.initials: SC
authors.lastname: Warren
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Morghan C
authors.identifier: 0000-0001-7654-9137
authors.initials: MC
authors.lastname: Lucas
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: David
authors.identifier: 0000-0002-9514-7501
authors.initials: D
authors.lastname: Herrmann
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Astrid
authors.initials: A
authors.lastname: Magenau
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Pauline
authors.identifier: 0000-0001-6486-2003
authors.initials: P
authors.lastname: Melenec
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Stacey N
authors.identifier: 0000-0001-5937-2341
authors.initials: SN
authors.lastname: Walters
authors.affiliation: St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.|Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Gonzalo
authors.identifier: 0000-0003-3830-2226
authors.initials: G
authors.lastname: Del Monte-Nieto
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: James R W
authors.initials: JR
authors.lastname: Conway
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Max
authors.identifier: 0000-0002-1861-1390
authors.initials: M
authors.lastname: Nobis
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Allam
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Rachael A
authors.identifier: 0000-0001-7791-4044
authors.initials: RA
authors.lastname: McCloy
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Currey
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Mark
authors.identifier: 0000-0001-5078-6687
authors.initials: M
authors.lastname: Pinese
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Alice
authors.initials: A
authors.lastname: Boulghourjian
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Anaiis
authors.initials: A
authors.lastname: Zaratzian
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Arne A S
authors.initials: AA
authors.lastname: Adam
authors.affiliation: Biomedical Imaging Facility, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
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authors.initials: C
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Adnan M
authors.initials: AM
authors.lastname: Nagrial
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.|Department of Pathology, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Chou
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Steinmann
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Alison
authors.identifier: 0000-0002-4858-0724
authors.initials: A
authors.lastname: Drury
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Danielle
authors.identifier: 0000-0001-9043-8935
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Marc
authors.identifier: 0000-0001-9043-8935
authors.initials: M
authors.lastname: Giry-Laterriere
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia.
authors.forename: Nathanial L E
authors.initials: NL
authors.lastname: Harris
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Tri
authors.identifier: 0000-0002-4909-2984
authors.initials: T
authors.lastname: Phan
authors.affiliation: Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia.|University of Sydney Medical School, Sydney, New South Wales 2006, Australia.
authors.forename: Rohit
authors.initials: R
authors.lastname: Jain
authors.affiliation: Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia.|University of Sydney Medical School, Sydney, New South Wales 2006, Australia.|Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
authors.forename: Ewan J
authors.initials: EJ
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authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Renee
authors.identifier: 0000-0002-6664-6344
authors.initials: R
authors.lastname: Whan
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.|University of Sydney, Sydney, New South Wales 2006, Australia.|Australian Pancreatic Cancer Genome Initiative.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Johns
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.|Australian Pancreatic Cancer Genome Initiative.|Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Samra
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Australian Pancreatic Cancer Genome Initiative.|Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Chantrill
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.|University of Sydney, Sydney, New South Wales 2006, Australia.|Australian Pancreatic Cancer Genome Initiative.|Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia.
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authors.identifier: 0000-0002-9447-1967
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.|School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia.
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authors.initials: M
authors.lastname: Kohonen-Corish
authors.affiliation: St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.|Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.|School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
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authors.initials: RP
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authors.affiliation: Australian Pancreatic Cancer Genome Initiative.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K.
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authors.identifier: 0000-0002-0362-5597
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authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
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authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
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authors.initials: KI
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
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authors.initials: ST
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
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authors.identifier: 0000-0002-2504-7919
authors.initials: CJ
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
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authors.identifier: 0000-0002-2347-7835
authors.initials: D
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authors.affiliation: Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA.
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authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.
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authors.identifier: 0000-0001-7880-6379
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authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
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authors.initials: OJ
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Andrew
authors.identifier: 0000-0003-4536-9226
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Thomas R
authors.identifier: 0000-0001-9294-1745
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authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
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authors.identifier: 0000-0001-5766-9141
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. m.pajic@garvan.org.au p.timpson@garvan.org.au.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
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authors.initials: M
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authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. m.pajic@garvan.org.au p.timpson@garvan.org.au.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000068196:Albumin-Bound Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015374:Biosensing Techniques; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003094:Collagen; D019061:src-Family Kinases; D054460:rho-Associated Kinases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C049347:fasudil; D000093542:Gemcitabine