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

Claire Vennin; Venessa T. Chin; Sean C. Warren; Morghan C. Lucas; David Herrmann; Astrid Magenau; Pauline Melenec; Stacey N. Walters; Gonzalo del Monte-Nieto; James R. W. Conway; Max Nobis; Amr H. Allam; Rachael A. McCloy; Nicola Currey; Mark Pinese; Alice Boulghourjian; Anaiis Zaratzian; Arne A. S. Adam; Celine Heu; Adnan M. Nagrial; Angela Chou; Angela Steinmann; Alison Drury; Danielle Froio; Marc Giry-Laterriere; Nathanial L. E. Harris; Tri Phan; Rohit Jain; Wolfgang Weninger; Ewan J. McGhee; Renee Whan; Amber L. Johns; Jaswinder S. Samra; Lorraine Chantrill; Anthony J. Gill; Maija Kohonen-Corish; Richard P. Harvey; Andrew V. Biankin; Australian Pancreatic Cancer Genome Initiative (APGI); T. R. Jeffry Evans; Kurt I. Anderson; Shane T. Grey; Christopher J. Ormandy; David Gallego-Ortega; Yingxiao Wang; Michael S. Samuel; Owen J. Sansom; Andrew Burgess; Thomas R. Cox; Jennifer P. Morton; Marina Pajic; Paul Timpson

doi:10.1126/scitranslmed.aai8504

Research ArticleCancer

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

Claire Vennin¹,²,*,
View ORCID ProfileVenessa T. Chin¹,²,*,
View ORCID ProfileSean C. Warren¹,²,†,
View ORCID ProfileMorghan C. Lucas¹,²,†,
View ORCID ProfileDavid Herrmann¹,²,
Astrid Magenau¹,²,
View ORCID ProfilePauline Melenec¹,²,
View ORCID ProfileStacey N. Walters¹,²,
View ORCID ProfileGonzalo del Monte-Nieto²,³,
James R. W. Conway¹,²,
View ORCID ProfileMax Nobis¹,²,
Amr H. Allam¹,²,
View ORCID ProfileRachael A. McCloy¹,²,
Nicola Currey¹,²,
View ORCID ProfileMark Pinese¹,²,
Alice Boulghourjian¹,
Anaiis Zaratzian¹,
Arne A. S. Adam³,
Celine Heu⁴,
Adnan M. Nagrial¹,
Angela Chou¹,²,⁵,
Angela Steinmann¹,
View ORCID ProfileAlison Drury¹,
Danielle Froio¹,
View ORCID ProfileMarc Giry-Laterriere¹,²,
Nathanial L. E. Harris¹,⁶,
View ORCID ProfileTri Phan¹,²,
Rohit Jain⁷,⁸,
Wolfgang Weninger⁷,⁸,⁹,
Ewan J. McGhee¹⁰,
View ORCID ProfileRenee Whan³,
Amber L. Johns¹,¹¹,¹²,¹³,
Jaswinder S. Samra¹⁰,¹³,¹⁴,
Lorraine Chantrill¹,¹³,¹⁴,
View ORCID ProfileAnthony J. Gill¹,¹¹,¹²,¹³,¹⁵,
Maija Kohonen-Corish¹,²,¹⁶,
Richard P. Harvey²,³,¹⁷,
View ORCID ProfileAndrew V. Biankin¹³,¹⁸,¹⁹,
Australian Pancreatic Cancer Genome Initiative (APGI)¹³,
T. R. Jeffry Evans¹⁰,
Kurt I. Anderson¹⁰,
Shane T. Grey¹,²,
Christopher J. Ormandy¹,²,
David Gallego-Ortega¹,²,
Yingxiao Wang²⁰,
Michael S. Samuel²¹,
Owen J. Sansom¹⁰,
Andrew Burgess¹,²,
Thomas R. Cox¹,²,
Jennifer P. Morton¹⁰,
Marina Pajic¹,²,*,‡ and
Paul Timpson¹,²,*,‡

¹The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
²St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
³Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
⁴Biomedical Imaging Facility, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
⁵Department of Pathology, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia.
⁶Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia.
⁷Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
⁸University of Sydney Medical School, Sydney, New South Wales 2006, Australia.
⁹Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
¹⁰Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
¹¹Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
¹²University of Sydney, Sydney, New South Wales 2006, Australia.
¹³Australian Pancreatic Cancer Genome Initiative
¹⁴Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
¹⁵Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia.
¹⁶School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia.
¹⁷School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
¹⁸Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K.
¹⁹West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K.
²⁰Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA.
²¹Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.

↵‡Corresponding author. Email: m.pajic{at}garvan.org.au (M. Pajic); p.timpson{at}garvan.org.au (P.T.)

↵* These authors contributed equally to this work.
↵† These authors contributed equally to this work.

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Science Translational Medicine 05 Apr 2017:
Vol. 9, Issue 384, eaai8504
DOI: 10.1126/scitranslmed.aai8504

Claire Vennin

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Venessa T. Chin

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Sean C. Warren

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Morghan C. Lucas

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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David Herrmann

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Astrid Magenau

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Pauline Melenec

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Stacey N. Walters

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Gonzalo del Monte-Nieto

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

3Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.

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James R. W. Conway

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Max Nobis

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Amr H. Allam

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Rachael A. McCloy

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Nicola Currey

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Mark Pinese

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Alice Boulghourjian

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

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Anaiis Zaratzian

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

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Arne A. S. Adam

3Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.

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Celine Heu

4Biomedical 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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Adnan M. Nagrial

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

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Angela Chou

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

5Department of Pathology, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia.

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Angela Steinmann

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

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Alison Drury

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

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Danielle Froio

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

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Marc Giry-Laterriere

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Nathanial L. E. Harris

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

6Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia.

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Tri Phan

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Rohit Jain

7Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia.

8University of Sydney Medical School, Sydney, New South Wales 2006, Australia.

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Wolfgang Weninger

7Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia.

8University of Sydney Medical School, Sydney, New South Wales 2006, Australia.

9Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.

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Ewan J. McGhee

10Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.

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Renee Whan

3Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.

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Amber L. Johns

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

11Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.

12University of Sydney, Sydney, New South Wales 2006, Australia.

13Australian Pancreatic Cancer Genome Initiative

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Jaswinder S. Samra

10Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.

13Australian Pancreatic Cancer Genome Initiative

14Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.

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Lorraine Chantrill

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

13Australian Pancreatic Cancer Genome Initiative

14Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.

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Anthony J. Gill

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

11Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.

12University of Sydney, Sydney, New South Wales 2006, Australia.

13Australian Pancreatic Cancer Genome Initiative

15Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia.

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Maija Kohonen-Corish

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

16School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia.

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Richard P. Harvey

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

3Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.

17School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia.

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Andrew V. Biankin

13Australian Pancreatic Cancer Genome Initiative

18Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K.

19West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K.

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13Australian Pancreatic Cancer Genome Initiative

T. R. Jeffry Evans

10Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.

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Kurt I. Anderson

10Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.

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Shane T. Grey

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Christopher J. Ormandy

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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David Gallego-Ortega

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Yingxiao Wang

20Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA.

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Michael S. Samuel

21Centre 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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Owen J. Sansom

10Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.

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Andrew Burgess

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Thomas R. Cox

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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Jennifer P. Morton

10Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.

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Marina Pajic

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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For correspondence: m.pajic@garvan.org.au p.timpson@garvan.org.au

Paul Timpson

1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.

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For correspondence: m.pajic@garvan.org.au p.timpson@garvan.org.au

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ROCK-ing pancreatic cancer to the core

Pancreatic cancer, one of the most deadly and difficult-to-treat tumor types in patients, usually has a dense stroma that can be difficult for drugs to penetrate. Stromal characteristics can also affect multiple other aspects of tumor biology, including metastatic spread, vascular supply, and immune response. Vennin et al. used Fasudil, a drug that inhibits a protein called ROCK and is already used for some conditions in people, to demonstrate the feasibility including short-term tumor stroma remodeling as part of cancer treatment. In genetically engineered and patient-derived mouse models of pancreatic cancer, priming with Fasudil disrupted the tumors’ extracellular matrix and improved the effectiveness of subsequent treatment with standard-of-care chemotherapy for this disease.

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

ROCK-ing pancreatic cancer to the core

Science Translational Medicine

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