BioProject

Pancreatic cancer patient survival is the lowest of all common cancers. Given that pancreatic cancer therapies do little to improve survival, there is a significant need to identify additional potential therapeutic targets and treatment strategies. More...

Pancreatic cancer patient survival is the lowest of all common cancers. Given that pancreatic cancer therapies do little to improve survival, there is a significant need to identify additional potential therapeutic targets and treatment strategies. The ROCK1 locus on chromosome 18 is amplified in 15% of pancreatic patient tumors (Biankin et al. 2012), accompanied by concordant copy number/gene expression changes (Bailey et al. 2016). The ROCK1 and ROCK2 kinases promote actomyosin contractility through phosphorylation of substrates including the myosin regulatory light chain 2 (MLC2), myosin-binding subunit of the MLC phosphatase (MYPT1) and LIM kinases 1&2 (Rath and Olson 2012, Julian and Olson 2014). In addition to direct effects on the organization and dynamics of the actin cytoskeleton that impact cell morphology, ROCK-mediated cell contractility also affects gene transcription (Sanz-Moreno et al. 2011). How ROCK-mediated actomyosin contractility might contribute to pancreatic cancer by altering gene expression has not been established. In this study, mouse pancreatic ductal adenocarcinoma tumour cells were transduced with retrovirus encoding conditionally-activated estrogen-receptor hormone-binding domain (hbER) fusions with ROCK1 (ROCK1:ER) or ROCK2 (ROCK2:ER) kinase domains, or green fluorescent protein (GFP:ER). GFP:ER expressing cells were treated with ethanol vehicle or 1 M 4-hydroxytamoxifen (4HT) to identify any effects of the estrogen analogue, while ROCK1:ER and ROCK2:ER cells were treated with 1 M 4HT to activate the ER fusion proteins. RNA was isolated, and enriched for poly A+ transcripts prior to sequencing.Bailey, P., et al. (2016). Nature 531: 47-52.Biankin, A. V., et al. (2012). Nature 491: 399-405.Julian, L. and M. F. Olson (2014). Small GTPases 5: e29846.Rath, N. and M. F. Olson (2012). EMBO Rep 13: 900-908.Sanz-Moreno, V., et al. (2011). Cancer Cell 20: 229-245. Less...