Journal article

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pedro A Perez-Mancera, Alistair G Rust, Louise van der Weyden, Glen Kristiansen, Allen Li, Aaron L Sarver, Kevin AT Silverstein, Robert Gruetzmann, Daniela Aust, Petra Ruemmele, Thomas Knoesel, Colin Herd, Derek L Stemple, Ross Kettleborough, Jacqueline A Brosnan, Ang Li, Richard Morgan, Spencer Knight, Jun Yu, Shane Stegeman Show all



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 deubi..

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Awarded by NIH

Awarded by Wilhelm Sander Stiftung

Awarded by Deutsche Forschungsgemeinschaft

Awarded by Cancer Research UK


Funding 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 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. Additional support was obtained from Fundacion Ibercaja (P.A.P.-M.).