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

Chin, Venessa T., Vennin, Claire, Warren, Sean C., Lucas, Morghan C., Herrmann, David, Magenau, Astrid, Melenec, Pauline, Walters, Stacey N., Monte-Nieto, Gonzalo dl, Conway, James R. W., Nobis, Max, Allam, Amr H., McCloy, Rachael A., Currey, Nicola, Pinese, Mark, Boulghourjian, Alice, Zaratzian, Anaiis, Adam, Arne A. S., Heu, Celine, Nagrial, Adnan M., Chou, Angela, Steinmann, Angela, Drury, Alison, Froio, Danielle, Giry-Laterriere, Marc, Harris, Nathanial L. E., Phan, Tri, Jain, Rohit, Weninger, Wolfgang, McGhee, Ewan J., Whan, Renee, Johns, Amber L., Samra, Jaswinder S., Chantrill, Lorraine, Gill, Anthony J., Kohonen-Corish, Maija, Harvey, Richard P., Biankin, Andrew V., Evans, T. R. Jeffry, Anderson, Kurt I., Grey, Shane T., Ormandy, Christopher J., Gallego-Ortega, David, Wang, Yingxiao, Samuel, Michael S., Sansom, Owen J., Burgess, Andrew, Cox, Thomas R., Morton, Jennifer P., Pajic, Marina and Timpson, Paul (2017) Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Science Translational Medicine, 9 384: . doi:10.1126/scitranslmed.aai8504

Author Chin, Venessa T.
Vennin, Claire
Warren, Sean C.
Lucas, Morghan C.
Herrmann, David
Magenau, Astrid
Melenec, Pauline
Walters, Stacey N.
Monte-Nieto, Gonzalo dl
Conway, James R. W.
Nobis, Max
Allam, Amr H.
McCloy, Rachael A.
Currey, Nicola
Pinese, Mark
Boulghourjian, Alice
Zaratzian, Anaiis
Adam, Arne A. S.
Heu, Celine
Nagrial, Adnan M.
Chou, Angela
Steinmann, Angela
Drury, Alison
Froio, Danielle
Giry-Laterriere, Marc
Harris, Nathanial L. E.
Phan, Tri
Jain, Rohit
Weninger, Wolfgang
McGhee, Ewan J.
Whan, Renee
Johns, Amber L.
Samra, Jaswinder S.
Chantrill, Lorraine
Gill, Anthony J.
Kohonen-Corish, Maija
Harvey, Richard P.
Biankin, Andrew V.
Evans, T. R. Jeffry
Anderson, Kurt I.
Grey, Shane T.
Ormandy, Christopher J.
Gallego-Ortega, David
Wang, Yingxiao
Samuel, Michael S.
Sansom, Owen J.
Burgess, Andrew
Cox, Thomas R.
Morton, Jennifer P.
Pajic, Marina
Timpson, Paul
Title Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis
Journal name Science Translational Medicine   Check publisher's open access policy
ISSN 1946-6234
Publication date 2017-04-05
Sub-type Article (original research)
DOI 10.1126/scitranslmed.aai8504
Open Access Status Not yet assessed
Volume 9
Issue 384
Total pages 17
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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