Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis
Authors listClaire Vennin Venessa T Chin Sean C Warren Morghan C Lucas David Herrmann Astrid Magenau Pauline Melenec Stacey N Walters Gonzalo Del Monte-Nieto James RW Conway Max Nobis Amr H Allam Rachael A McCloy Nicola Currey Mark Pinese Alice Boulghourjian Anaiis Zaratzian Arne AS Adam Celine Heu Adnan M Nagrial Angela Chou Angela Steinmann Alison Drury Danielle Froio Marc Giry-Laterriere Nathanial LE 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 Australian Pancreatic Cancer Genome Initiative (APGI) TR Jeffry Evans Kurt 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
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.