Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis
| Autor: | Renee Whan, Danielle Froio, Andrew Burgess, Rohit Jain, David Gallego-Ortega, Paul Timpson, Maija R.J. Kohonen-Corish, Pauline Mélénec, Amr H. Allam, Shane T. Grey, Sean C. Warren, Thomas R. Cox, Anthony J. Gill, Amber L. Johns, Anaiis Zaratzian, Jaswinder S. Samra, Celine Heu, Morghan C. Lucas, Tri Giang Phan, Angela Steinmann, Lorraine A. Chantrill, Nathanial L. E. Harris, Alice Boulghourjian, Yingxiao Wang, Adnan Nagrial, Alison Drury, Arne A. S. Adam, Claire Vennin, Owen J. Sansom, Christopher J. Ormandy, Nicola Currey, Marina Pajic, Angela Chou, Michael S. Samuel, Stacey N. Walters, Wolfgang Weninger, T.R. Jeffry Evans, Venessa T. Chin, Kurt I. Anderson, Richard P. Harvey, James R.W. Conway, Andrew V. Biankin, Jennifer P. Morton, Astrid Magenau, Rachael A. McCloy, Ewan J. McGhee, Max Nobis, David Herrmann, Marc Giry-Laterriere, Gonzalo del Monte-Nieto, Mark Pinese |
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| Přispěvatelé: | Vennin, Claire, Chin, Venessa T, Warren, Sean C, Lucas, Morghan C, Samuel, Michael S, Timpson, Paul, Australian Pancreatic Cancer Genome Initiative (APGI) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_treatment pancreatic cancer Priming (immunology) Biosensing Techniques Deoxycytidine Metastasis Mice 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Neoplasm Metastasis rho-Associated Kinases Kinase gemcitabine Fasudil General Medicine Extracellular Matrix Actin Cytoskeleton Treatment Outcome src-Family Kinases Medicine Research & Experimental Liver Disease Progression Collagen medicine.drug Signal Transduction medicine.medical_specialty Antineoplastic Agents cancer growth 03 medical and health sciences Pancreatic cancer Cell Line Tumor CDC2 Protein Kinase medicine metastasis Animals Humans Neoplasm Invasiveness Protein Kinase Inhibitors Cell Proliferation Chemotherapy business.industry Cell Biology medicine.disease Gemcitabine Pancreatic Neoplasms 030104 developmental biology Rho kinase inhibitor Cancer research Albumin-Bound Paclitaxel business |
| Zdroj: | Science translational medicine. 9(384) |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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