title: ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth.
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/p53R172Hmouse 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/p53R172HPDAC 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.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Rath
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Julian
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Lena
authors.initials: L
authors.lastname: Helbig
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Shereen
authors.initials: S
authors.lastname: Kadir
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Ewan J
authors.initials: EJ
authors.lastname: McGhee
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.affiliation: Electron Microscopy Facility, School of Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Mullin
authors.affiliation: Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Andreia V
authors.initials: AV
authors.lastname: Pinho
authors.affiliation: Oncology Research Centre, Free University Brussels (VUB), Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK m.olson@beatson.gla.ac.uk.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Michael F
authors.identifier: 0000-0003-3428-3507
authors.initials: MF
authors.lastname: Olson
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D003094:Collagen / Q000378:metabolism*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D016019:Survival Analysis; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D003094:Collagen; D054460:rho-Associated Kinases
keywords: ROCK kinases; collagen remodeling; extracellular matrix; pancreatic cancer; tumor cell invasion