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

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

Sci Transl Med. 2017 Apr 5;9(384):eaai8504. doi: 10.1126/scitranslmed.aai8504.

Authors

Claire Vennin^{1

2}, Venessa T Chin^{1

2}, Sean C Warren^{1

2}, Morghan C Lucas^{1

2}, David Herrmann^{1

2}, Astrid Magenau^{1

2}, Pauline Melenec^{1

2}, Stacey N Walters^{1

2}, Gonzalo Del Monte-Nieto^{2

3}, James R W Conway^{1

2}, Max Nobis^{1

2}, Amr H Allam^{1

2}, Rachael A McCloy^{1

2}, Nicola Currey^{1

2}, Mark Pinese^{1

2}, Alice Boulghourjian¹, Anaiis Zaratzian¹, Arne A S Adam³, Celine Heu⁴, Adnan M Nagrial¹, Angela Chou^{1

2

5}, Angela Steinmann¹, Alison Drury¹, Danielle Froio¹, Marc Giry-Laterriere^{1

2}, Nathanial L E Harris^{1

6}, Tri Phan^{1

2}, Rohit Jain^{7

8}, Wolfgang Weninger^{7

8

9}, Ewan J McGhee¹⁰, Renee Whan³, Amber L Johns^{1

11

12

13}, Jaswinder S Samra^{10

13

14}, Lorraine Chantrill^{1

13

14}, Anthony J Gill^{1

11

12

13

15}, Maija Kohonen-Corish^{1

2

16}, Richard P Harvey^{2

3

17}, Andrew V Biankin^{13

18

19}; Australian Pancreatic Cancer Genome Initiative (APGI); T R Jeffry Evans¹⁰, Kurt I Anderson¹⁰, Shane T Grey^{1

2}, Christopher J Ormandy^{1

2}, David Gallego-Ortega^{1

2}, Yingxiao Wang²⁰, Michael S Samuel²¹, Owen J Sansom¹⁰, Andrew Burgess^{1

2}, Thomas R Cox^{1

2}, Jennifer P Morton¹⁰, Marina Pajic^{22

2}, Paul Timpson^{22

2}

Affiliations

¹ The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
² St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
³ Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
⁴ Biomedical Imaging Facility, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
⁵ Department of Pathology, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia.
⁶ Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia.
⁷ Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
⁸ University of Sydney Medical School, Sydney, New South Wales 2006, Australia.
⁹ Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
¹⁰ Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K.
¹¹ Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
¹² University of Sydney, Sydney, New South Wales 2006, Australia.
¹³ Australian Pancreatic Cancer Genome Initiative.
¹⁴ Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
¹⁵ Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia.
¹⁶ School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia.
¹⁷ School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
¹⁸ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K.
¹⁹ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K.
²⁰ Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA.
²¹ Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.
²² 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
Actin Cytoskeleton / drug effects
Actin Cytoskeleton / metabolism
Albumin-Bound Paclitaxel / pharmacology
Albumin-Bound Paclitaxel / therapeutic use
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Biosensing Techniques
CDC2 Protein Kinase / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Collagen / metabolism
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Deoxycytidine / therapeutic use
Disease Progression*
Extracellular Matrix / metabolism
Gemcitabine
Humans
Liver / pathology
Mice
Neoplasm Invasiveness
Neoplasm Metastasis
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / pathology*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use*
Signal Transduction / drug effects
Treatment Outcome
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / metabolism
src-Family Kinases / metabolism

Substances

Albumin-Bound Paclitaxel
Antineoplastic Agents
Protein Kinase Inhibitors
Deoxycytidine
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
Collagen
src-Family Kinases
rho-Associated Kinases
CDC2 Protein Kinase
CDK1 protein, human
fasudil
Gemcitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding