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

Nicola Rath, Jennifer P. Morton, Linda Julian, Lena Helbig, Shereen Kadir, Ewan J. McGhee, Kurt I. Anderson, Gabriela Kalna, Margaret Mullin, Andreia V. Pinho, Ilse Rooman, Michael S. Samuel, Michael F. Olson

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages198-218
Number of pages21
JournalEMBO Molecular Medicine
Volume9
Issue number2
DOIs
Publication statusPublished - 1 Feb 2017
Externally publishedYes

Fingerprint

Adenocarcinoma
Collagen
Growth
Neoplasms
Matrix Metalloproteinases
Extracellular Matrix
RNA Sequence Analysis
Actomyosin
Survival
Pancreatic Neoplasms
Cause of Death
Phosphotransferases
Therapeutics
Genes

Bibliographical note

Copyright Cancer Research UK Beatson Institute 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

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

Cite this

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. / ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 2. pp. 198-218.
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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.",
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Rath, N, Morton, JP, Julian, L, Helbig, L, Kadir, S, McGhee, EJ, Anderson, KI, Kalna, G, Mullin, M, Pinho, AV, Rooman, I, Samuel, MS & Olson, MF 2017, 'ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth', EMBO Molecular Medicine, vol. 9, no. 2, pp. 198-218. https://doi.org/10.15252/emmm.201606743

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

In: EMBO Molecular Medicine, Vol. 9, No. 2, 01.02.2017, p. 198-218.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Rooman, Ilse

AU - Samuel, Michael S.

AU - Olson, Michael F.

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