Open AccessROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth
Author(s) -
Rath Nicola,
Morton Jennifer P,
Julian Linda,
Helbig Lena,
Kadir Shereen,
McGhee Ewan J,
Anderson Kurt I,
Kalna Gabriela,
Mullin Margaret,
Pinho Andreia V,
Rooman Ilse,
Samuel Michael S,
Olson Michael F
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606743
Subject(s) - cancer , library science , pancreatic cancer , medicine , computer science
Pancreatic ductal adenocarcinoma ( PDAC ) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK 1 and ROCK 2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK 1/ ROCK 2 expression in human patients, or conditional ROCK 2 activation in a Kras G12D / p53 R172H mouse PDAC model, was associated with reduced survival. Conditional ROCK 1 or ROCK 2 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 Kras G12D / p53 R172H 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.