ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth

Rath, N. et al. (2017) ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. EMBO Molecular Medicine, 9(2), pp. 198-218. (doi: 10.15252/emmm.201606743) (PMID:28031255) (PMCID:PMC5286371)

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Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a KrasG12D/p53R172H mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three‐dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK‐induced genes that facilitate extracellular matrix remodeling, with greatest fold‐changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13. MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three‐dimensional contexts. Treatment of KrasG12D/p53R172H PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor‐associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth.

Item Type:Articles
Additional Information:Funding from Cancer Research UK (A18276). N.R. received a Cancer Research UK Research Travel Award and a Company of Biologists Travelling Fellowship.
Glasgow Author(s) Enlighten ID:Anderson, Professor Kurt and McGhee, Dr Ewan and Rath, Dr Nicola and Kadir, Dr Shereen and Kalna, Dr Gabriela and Morton, Professor Jen and Mullin, Mrs Margaret and Olson, Professor Michael
Authors: Rath, N., Morton, J. P., Julian, L., Helbig, L., Kadir, S., McGhee, E. J., Anderson, K. I., Kalna, G., Mullin, M., Pinho, A. V., Rooman, I., Samuel, M. S., and Olson, M. F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:EMBO Molecular Medicine
Publisher:EMBO Press
ISSN (Online):1757-4684
Published Online:28 December 2016
Copyright Holders:Copyright © 2016 Cancer Research UK Beatson Institute
First Published:First published in EMBO Molecular Medicine 9(2): 198-218
Publisher Policy:Reproduced under a Creative Commons License

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