ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth
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.
|ISBN||1757-4684 (Electronic) 1757-4676 (Linking)|
|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.; Olson, M. F.|
|Publisher Name||EMBO Molecular Medicine|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/28031255|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14303|