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The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Nature volume 486, pages 266–270 (2012)Cite this article

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A Corrigendum to this article was published on 30 January 2013

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations1,2,3,4 in addition to numerous lower frequency genetic events of uncertain significance5. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis6,7 in a mouse model of pancreatic ductal preneoplasia8 to identify genes that cooperate with oncogenic KrasG12D 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 neoplasia9, 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-2′-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.

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Figure 1: Transposon mutagenesis accelerates murine PDA and targets Usp9x.
Figure 2: Usp9x regulates PDA cellular transformation and Itch.
Figure 3: USP9X loss promotes PDA.

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Gene Expression Omnibus

Data deposits

The GEO accession number for the ICGC/APGI gene expression data is GSE36924.

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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 SPORE grant to D.A.T., D.A.L. and C.A.I.-D.; grants CA62924, CA128920 and CA106610 to C.A.I.-D.; P50CA62924 SPORE grant to 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. and the APGI investigators are funded by the University of Verona and Italian Ministry of University and Research (FIRB RBAP10AHJB); the National Health and Medical 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. S.A.W. was supported by the NHMRC. Additional support was obtained from Fundación Ibercaja (P.A.P.-M.).

Author information

Author notes

  1. Christine A. Iacobuzio-Donahue, Christian Pilarsky and David A. Largaespada: These authors contributed equally to this work.

Authors and Affiliations

  1. and Department of Oncology, Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Robinson Way, Cambridge CB2 0RE, UK,

    Pedro A. Pérez-Mancera & David A. Tuveson

  2. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK,

    Alistair G. Rust, Louise van der Weyden & David J. Adams

  3. Institute of Pathology, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany,

    Glen Kristiansen

  4. Departments of Oncology and Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, 21231, Maryland, USA

    Allen Li, Jacqueline A. Brosnan, Ang Li, Richard Morgan, Spencer Knight, Jun Yu, Alison P. Klein, Michael Goggins, Ralph H. Hruban & Christine A. Iacobuzio-Donahue

  5. Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, 425 Delaware St SE MMC 806, Minneapolis, Minnesota 55455, USA,

    Aaron L. Sarver & Kevin A. T. Silverstein

  6. Department of Surgery, University Hospital Dresden, Fetscherstr. 74, 01307 Dresden, Germany,

    Robert Grützmann & Christian Pilarsky

  7. Institute of Pathology, University Hospital Dresden, Fetscherstr. 74, 01307 Dresden, Germany,

    Daniela Aust

  8. Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany,

    Petra Rümmele

  9. Institute of Pathology, University Hospital of Jena, Bachstraße 18, 07743 Jena, Germany,

    Thomas Knösel

  10. Institute of Pathology, Ludwig-Maximilians-University (LMU), Thalkirchnerstr. 36, 80337 Munich, Germany,

    Thomas Knösel

  11. Vertebrate Development and Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK,

    Colin Herd, Derek L. Stemple & Ross Kettleborough

  12. Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia,

    Shane Stegeman & Stephen A. Wood

  13. School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA,

    Lara S. Collier

  14. Delft Bioinformatics Lab, Faculty of EEMCS, Delft University of Technology, 2628 CD Delft, The Netherlands,

    Jelle J. ten Hoeve, Jeroen de Ridder & Lodewyk F. A. Wessels

  15. Bioinformatics and Statistics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands,

    Jelle J. ten Hoeve & Lodewyk F. A. Wessels

  16. The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, 372 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia,

    David K. Chang & Andrew V. Biankin

  17. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia,

    David K. Chang & Andrew V. Biankin

  18. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales 2170, Australia,

    David K. Chang & Andrew V. Biankin

  19. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia,

    Sean M. Grimmond

  20. Masonic Cancer Center, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    David A. Largaespada

  21. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 372 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.,

    Andrew V. Biankin, Amber L. Johns, Amanda Mawson, David K. Chang, 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, Christopher J. Scarlett & Warren Kaplan

  22. Queensland Center for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.,

    Sean M. Grimmond, 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

  23. Royal North Shore Hospital, Westbourne Street, Saint Leonards, New South Wales 2065, Australia.,

    Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski & Christopher Toon

  24. Bankstown Hospital, Eldridge Road, Bankstown, New South Wales 2200, Australia.,

    Andrew V. Blankin, Ray Asghari, Neil D. Merrett, David K. Chang, Darren A. Pavey & Amitabha Das

  25. Liverpool Hospital, Elizabeth Street, Liverpool, New South Wales 2170, Australia.,

    Peter H. Cosman, Kasim Ismail & Chelsie O’Connor

  26. Westmead Hospital, Corner of Hawkesbury and Darcy Roads, Westmead, New South Wales 2145, Australia.,

    Vincent W. Lam, Duncan McLeod, Henry C. Pleass & Virginia James

  27. Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia.,

    James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi & Michael Crawford

  28. Fremantle Hospital, Alma Street, Fremantle, Western Australia 6959, Australia.,

    Michael Texler, Cindy Forrest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher & Sanjay Mukhedkar

  29. Sir Charles Gardiner Hospital, Hospital Avenue, Nedlands, Western Australia 6009, Australia.,

    Nigel A. Spry, Bastiaan DeBoer, Ming Chai & Kynan Feeney

  30. St John of God Healthcare, 12 Salvado Road, Subiaco, Western Australia 6008, Australia.,

    Nikolajs Zeps & Maria Beilin

  31. Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.,

    Nam Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan & Tamara Debrencini

  32. Flinders Medical Center, Flinders Drive, Bedford Park, South Australia 5042, Australia.,

    John Chen, Mark E. Brooke-Smith & Virginia Papangelis

  33. Greenslopes Private Hospital, Newdegate Street, Greenslopes, Queensland 4120, Australia.,

    Henry Tang & Andrew P. Barbour

  34. Envoi Pathology, 1/49 Butterfield Street, Herston, Queensland 4006, Australia.,

    Andrew D. Clouston & Patrick Martin

  35. Princess Alexandria Hospital, Corner of Cornwall Street and Ipswich Road, Woolloongabba, Queensland 4102, Australia.,

    Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis & Peter Hodgkinson

  36. Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia.,

    Christopher Christophi & Mehrdad Nikfarjam

  37. Victorian Cancer Biobank, 1 Rathdowne Street, Carlton, Victoria 3053, Australia.,

    Victorian Cancer Biobank

  38. Johns Hopkins Medical Institutes, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.,

    James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang & Richard A. Morgan

  39. ARC-NET Center for Applied Research on Cancer, University of Verona, Policlinico GB Rossi, Piazzale LA Scuro 10, 37134 Verona, Italy.,

    Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi & Aldo Scarpa

  40. University of California, San Francisco, 500 Parnassus Avenue, San Francisco, California 94122, USA.,

    Margaret A. Tempero

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Australian Pancreatic Cancer Genome Initiative

  • Garvan Institute of Medical Research

    • Andrew V. Biankin
    • , Amber L. Johns
    • , Amanda Mawson
    • , David K. Chang
    • , 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
    • , Christopher J. Scarlett
    •  & Warren Kaplan

  • Queensland Center for Medical Genomics, Institute for Molecular Bioscience

    • Sean M. Grimmond
    • , 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
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    • , Darrin Taylor
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    • , Tim Bruxner
    • , Nicole Cloonan
    • , Felicity Newell
    •  & John V. Pearson

  • Royal North Shore Hospital

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    • , Anthony J. Gill
    • , Nick Pavlakis
    • , Alex Guminski
    •  & Christopher Toon

  • Bankstown Hospital

    • Andrew V. Blankin
    • , Ray Asghari
    • , Neil D. Merrett
    • , David K. Chang
    • , Darren A. Pavey
    •  & Amitabha Das

  • Liverpool Hospital

    • Peter H. Cosman
    • , Kasim Ismail
    •  & Chelsie O’Connor

  • Westmead Hospital

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  • Royal Adelaide Hospital

    • Nam Q. Nguyen
    • , Andrew R. Ruszkiewicz
    • , Chris Worthley
    • , Chuan P. Tan
    •  & Tamara Debrencini

  • Flinders Medical Center

    • John Chen
    • , Mark E. Brooke-Smith
    •  & Virginia Papangelis

  • Greenslopes Private Hospital

    • Henry Tang
    •  & Andrew P. Barbour

  • Envoi Pathology

    • Andrew D. Clouston
    •  & Patrick Martin

  • Princess Alexanda Hospital

    • Thomas J. O’Rourke
    • , Amy Chiang
    • , Jonathan W. Fawcett
    • , Kellee Slater
    • , Shinn Yeung
    • , Michael Hatzifotis
    •  & Peter Hodgkinson

  • Austin Hospital

    • Christopher Christophi
    • , Mehrdad Nikfarjam
    •  & Victorian Cancer Biobank

  • Johns Hopkins Medical Institutes

    • James R. Eshleman
    • , Ralph H. Hruban
    • , Anirban Maitra
    • , Christine A. Iacobuzio-Donahue
    • , Richard D. Schulick
    • , Christopher L. Wolfgang
    •  & Richard A. Morgan

  • ARC-NET Center for Applied Research on Cancer

    • Rita T. Lawlor
    • , Stefania Beghelli
    • , Vincenzo Corbo
    • , Maria Scardoni
    • , Claudio Bassi
    •  & Aldo Scarpa

  • University of California

    • Margaret A. Tempero

Contributions

P.A.P.-M. performed the majority of all experiments, designed experiments, analysed data, and wrote the manuscript. L.v.d.W. and J.A.B. performed in vitro experiments. S.S. and S.A.W. generated the conditional Usp9x mouse. L.S.C. provided the CAGGS-SB10 and T2/Onc mice. A.G.R., A.L.S., K.A.T.S., J.J.t.H., J.d.R. and L.F.A.W. conducted the CIS data analysis. G.K., R.G., D.A., P.R., T.K. and C.P. generated data from resected pancreatic tumours. Allen Li, R.H.H., R.M., S.K., J.Y., Ang Li, M.G. and C.A.I.-D. analysed human samples from autopsy series, and analysed mouse pathology and methylation studies. C.H., D.L.S. and R.K. sequenced PDA human samples from autopsy series. A.P.K. provided statistical analyses for the human PDA data sets. APGI, D.K.C., S.M.G. and A.V.B. generated and analysed data from ICGC/APGI (International Cancer Genome Consortium/Australian Pancreatic Cancer Genome Initiative). D.A.L. provided the CAGGS-SB10 and T2/Onc mice, and analysed data. D.J.A. and D.A.T. designed the study, analysed the data, and wrote the manuscript. All authors commented upon and edited the final manuscript.

Corresponding authors

Correspondence to David J. Adams or David A. Tuveson.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-19, Supplementary Tables 1 and 5-11, full legends for Tables 2-4 and an additional reference. (PDF 15995 kb)

Supplementary Table 2

This table shows candidate CIS genes in pancreas tumours from KCTSB13 mice. (XLS 264 kb)

Supplementary Table 3

This file contains Supplementary Tables 3a and 3b as BED files which list non-redundant insertions. (ZIP 1026 kb)

Supplementary Table 4

This table shows comparison of KCTSB13 CISs to prior work in human PDA. (XLS 228 kb)

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Pérez-Mancera, P., Rust, A., van der Weyden, L. et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 486, 266–270 (2012). https://doi.org/10.1038/nature11114

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