A1 Refereed original research article in a scientific journal
Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis
Authors: Chin VT, Vennin C, Warren SC, Lucas MC, Herrmann D, Magenau A, Melenec P, Walters SN, Monte-Nieto GD, Conway JRW, Nobis M, Allam AH, McCloy RA, Currey N, Pinese M, Boulghourjian A, Zaratzian A, Adam AAS, Heu C, Nagrial AM, Chou A, Steinmann A, Drury A, Froio D, Giry-Laterriere M, Harris NLE, Phan T, Jain R, Weninger W, McGhee EJ, Whan R, Johns AL, Samra JS, Chantrill L, Gill AJ, Kohonen-Corish M, Harvey RP, Biankin AV, Evans TRJ, Anderson KI, Grey ST, Ormandy CJ, Gallego-Ortega D, Wang YX, Samuel MS, Sansom OJ, Burgess A, Cox TR, Morton JP, Pajic M, Timpson P
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publication year: 2017
Journal: Science Translational Medicine
Journal name in source: SCIENCE TRANSLATIONAL MEDICINE
Journal acronym: SCI TRANSL MED
Article number: ARTN eaai8504
Volume: 9
Issue: 384
Number of pages: 17
ISSN: 1946-6234
DOI: https://doi.org/10.1126/scitranslmed.aai8504
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 Forster 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.
