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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606743 |
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| _version_ | 1849343427260448768 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nicola Rath |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-965beffc5d8b4fb09500eba6469b356a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-965beffc5d8b4fb09500eba6469b356a2025-08-20T03:43:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-12-019219821810.15252/emmm.201606743ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growthNicola Rath0Jennifer P Morton1Linda Julian2Lena Helbig3Shereen Kadir4Ewan J McGhee5Kurt I Anderson6Gabriela Kalna7Margaret Mullin8Andreia V Pinho9Ilse Rooman10Michael S Samuel11Michael F Olson12Cancer Research UK Beatson InstituteCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteElectron Microscopy Facility, School of Life Sciences, University of GlasgowCancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical ResearchOncology Research Centre, Free University Brussels (VUB)Centre for Cancer Biology, SA Pathology and the University of South AustraliaCancer Research UK Beatson InstituteAbstract 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.https://doi.org/10.15252/emmm.201606743collagen remodelingextracellular matrixpancreatic cancerROCK kinasestumor cell invasion |
| spellingShingle | 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 ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth EMBO Molecular Medicine collagen remodeling extracellular matrix pancreatic cancer ROCK kinases tumor cell invasion |
| title | ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth |
| title_full | ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth |
| title_fullStr | ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth |
| title_full_unstemmed | ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth |
| title_short | ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth |
| title_sort | rock signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth |
| topic | collagen remodeling extracellular matrix pancreatic cancer ROCK kinases tumor cell invasion |
| url | https://doi.org/10.15252/emmm.201606743 |
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