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. NagrialAngela 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, 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

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93 Citations (Scopus)

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.

Original languageEnglish
Article numbereaai8504
Number of pages17
JournalScience Translational Medicine
Volume9
Issue number384
DOIs
Publication statusPublished - 5 Apr 2017
Externally publishedYes

Cite this

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., ... Timpson, P. (2017). Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Science Translational Medicine, 9(384), [eaai8504]. https://doi.org/10.1126/scitranslmed.aai8504