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

Claire Vennin(Garvan Institute of Medical Research), Venessa Chin(Garvan Institute of Medical Research), Sean Warren(Garvan Institute of Medical Research), Morghan C. Lucas(Garvan Institute of Medical Research), David Herrmann(Garvan Institute of Medical Research), Astrid Magenau(Garvan Institute of Medical Research), Pauline Mélénec(Garvan Institute of Medical Research), Stacey N. Walters(Garvan Institute of Medical Research), Gonzalo del Monte‐Nieto(Victor Chang Cardiac Research Institute), James R. W. Conway(Garvan Institute of Medical Research), Max Nobis(Garvan Institute of Medical Research), Amr H. Allam(Garvan Institute of Medical Research), Rachael A. McCloy(Garvan Institute of Medical Research), Nicola Currey(Garvan Institute of Medical Research), Mark Pinese(Garvan Institute of Medical Research), Alice Boulghourjian(Garvan Institute of Medical Research), Anaiis Zaratzian(Garvan Institute of Medical Research), Arne A. S. Adam(Victor Chang Cardiac Research Institute), Céline Heu(UNSW Sydney), Adnan Nagrial(Garvan Institute of Medical Research), Angela Chou(Garvan Institute of Medical Research), Angela Steinmann(Garvan Institute of Medical Research), Alison Drury(Garvan Institute of Medical Research), Danielle Froio(Garvan Institute of Medical Research), Marc Giry-Laterrière(Garvan Institute of Medical Research), Nathanial Lachlan Ewart Harris(Garvan Institute of Medical Research), Tri Giang Phan(Garvan Institute of Medical Research), Rohit Jain(The University of Sydney), Wolfgang Weninger(The University of Sydney), Ewan J. McGhee(Cancer Research UK Scotland Institute), Renée Whan(Victor Chang Cardiac Research Institute), Amber L. Johns(The University of Sydney), Jaswinder S. Samra(Royal North Shore Hospital), Lorraine A. Chantrill(Garvan Institute of Medical Research), Anthony J. Gill(Camden and Campbelltown Hospitals), Maija R.J. Kohonen‐Corish(Garvan Institute of Medical Research), Richard P. Harvey(Victor Chang Cardiac Research Institute), Andrew V. Biankin(Beatson West of Scotland Cancer Centre), Australian Pancreatic Cancer Genome Initiative (APGI)(Cancer Research UK Scotland Institute), T.R. Jeffry Evans(Cancer Research UK Scotland Institute), Kurt I. Anderson(Garvan Institute of Medical Research), Shane T. Grey(Garvan Institute of Medical Research), Christopher J. Ormandy(Garvan Institute of Medical Research), David Gallego‐Ortega(Garvan Institute of Medical Research), Yingxiao Wang(University of San Diego), Michael S. Samuel(Centre for Cancer Biology), Owen J. Sansom(Garvan Institute of Medical Research), Andrew Burgess(Garvan Institute of Medical Research), Thomas R. Cox(Garvan Institute of Medical Research), Jennifer P. Morton(Garvan Institute of Medical Research), Marina Pajic(Garvan Institute of Medical Research), Paul Timpson(Garvan Institute of Medical Research)
Science Translational Medicine
April 5, 2017
10.1126/scitranslmed.aai8504
Cited by 266

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.

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