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

Vennin, C. et al. (2017) Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Science Translational Medicine, 9(384), eaai8504. (doi: 10.1126/scitranslmed.aai8504) (PMID:28381539) (PMCID:PMC5777504)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Anderson, Professor Kurt and Biankin, Professor Andrew and McGhee, Dr Ewan and Evans, Professor Jeff and Morton, Professor Jen and Sansom, Professor Owen
• Authors: Vennin, C., Chin, V. T., Warren, S. C., Lucas, M. C., Herrmann, D., Magenau, A., Melenec, P., Walters, S. N., Del Monte-Nieto, G., Conway, J. R.W., Nobis, M., Allam, A. H., McCloy, R. A., Currey, N., Pinese, M., Boulghourjian, A., Zaratzian, A., Adam, A. A.S., Heu, C., Nagrial, A. M., Chou, A., Steinmann, A., Drury, A., Froio, D., Giry-Laterriere, M., Harris, N. L.E., Phan, T., Jain, R., Weninger, W., McGhee, E. J., Whan, R., Johns, A. L., Samra, J. S., Chantrill, L., Gill, A. J., Kohonen-Corish, M., Harvey, R. P., Biankin, A. V., Evans, T.R. J., Anderson, K. I., Grey, S. T., Ormandy, C. J., Gallego-Ortega, D., Wang, Y., Samuel, M. S./, Sansom, O. J., Burgess, A., Cox, T. R./, Morton, J. P., Pajic, M., and Timpson, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science Translational Medicine
• Publisher: American Association for the Advancement of Science
• ISSN: 1946-6234
• ISSN (Online): 1946-6242
• Copyright Holders: Copyright © 2017 American Association for the Advancement of Science
• First Published: First published in Science Translational Medicine 9(384):eaai8504
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher