The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pedro A. Pérez-Mancera, Alistair G. Rust, Louise Van Der Weyden, Glen Kristiansen, Allen Li, Aaron L. Sarver, Kevin A T Silverstein, Robert Grützmann, Daniela Aust, Petra Rümmele, Thomas Knösel, Colin Herd, Derek L. Stemple, Ross Kettleborough, Jacqueline A. Brosnan, Ang Li, Richard Morgan, Spencer Knight, Jun Yu, Shane StegemanLara S. Collier, Jelle J. Ten Hoeve, Jeroen De Ridder, Alison P. Klein, Michael Goggins, Ralph H. Hruban, David K. Chang, Andrew V Wessels Biankin, Sean M. Grimmond, Lodewyk F A Wessels, Stephen A. Wood, Christine A. Iacobuzio-Donahue, Christian Pilarsky, David A. Largaespada, David J. Adams, David A. Tuveson, Andrew V. Bienkin, Amber L. Johns, Amanda Mawson, David K. Cheng, Mary Anne L Brancato, Sarah J. Rowe, Skye L. Simpson, Mona Martyn-Smith, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, Marc D. Jones, R. Scott Mead, Adnan M. Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Sean M. Grimond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Andrew V. Blankin, Ray Asghari, Neil D. Merrett, Darren A. Pavey, Amithabad Das, Peter H. Cosman, Kasim Ismail, Chelsie O'Connor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, Michael Texler, Cindy Forrest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan Deboer, Ming Chai, Kynan Feeney, Nikolajs Zeps, Maria Beilin, Nam Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O'Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Victorian Cancer Biobank, James R. Eshleman, Anirban Maitra, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero

Research output: Contribution to journalArticlepeer-review

223 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras G12D to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-22-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with KrasG12D to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

Original languageEnglish (US)
Pages (from-to)266-270
Number of pages5
JournalNature
Volume486
Issue number7402
DOIs
StatePublished - Jun 14 2012

Bibliographical note

Funding Information:
Acknowledgements We thank P. Labosky for assistance in generating the Rosa26-LSL-SB13 mouse; B. Bhagavan for pathology consultation; M. Tsao for providing the HPDE cell line; and N. Copeland and K. Mann for sharing pre-published information. We thank A. Gopinathan, H. Tiriac, D. Engle, D. Chan, F. Connor, S. Derkits and other members of the Tuveson laboratory for assistance and advice, and the animal care staff and histology core at CRI, and The University of Minnesota’s Mouse Genetics Laboratory. This research was supported by the University of Cambridge and Cancer Research UK, The Li Ka Shing Foundation and Hutchison Whampoa Limited, the NIHR Cambridge Biomedical Research Centre, and the NIH (2P50CA101955 SPOREgrant to D.A.T., D.A.L. andC.A.I.-D.; grants CA62924, CA128920 andCA106610 to C.A.I.-D.; P50CA62924 SPORE grantto R.H.H. and C.A.I.-D.; and CA122183 to L.S.C.). D.J.A. is supported by Cancer Research UK and the Wellcome Trust. L.v.d.W. is supported by the Kay Kendall Leukemia Fund. C.P. is supported by Wilhelm Sander Stiftung (2009.039.1) and Deutsche Forschungsgemeinschaft (PI 341/5-1). A.V.B., D.K.C., S.M.G. andthe APGIinvestigators are fundedbythe NationalHealthandMedical research Council of Australia (NHMRC); Queensland Government; Cancer Council NSW; Australian Cancer Research Foundation; Cancer Institute NSW; The Avner Nahmani Pancreatic Cancer Research Foundation; and the R.T. Hall Trust. Additional support was obtained from Fundación Ibercaja (P.A.P.-M.).

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