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EMBO Mol Med. 2016 Dec 28. pii: e201606743. doi: 10.15252/emmm.201606743. [Epub ahead of print]

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

Author information

  • 1Cancer Research UK Beatson Institute, Glasgow, UK.
  • 2Electron Microscopy Facility, School of Life Sciences, University of Glasgow, Glasgow, UK.
  • 3Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • 4Oncology Research Centre, Free University Brussels (VUB), Brussels, Belgium.
  • 5Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, Australia.
  • 6Cancer Research UK Beatson Institute, Glasgow, UK m.olson@beatson.gla.ac.uk.
  • 7Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Abstract

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.

KEYWORDS:

ROCK kinases; collagen remodeling; extracellular matrix; pancreatic cancer; tumor cell invasion

PMID:
28031255
DOI:
10.15252/emmm.201606743
[PubMed - as supplied by publisher]
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