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dc.contributor.authorA. Pérez-Mancera, Pedroen_US
dc.contributor.authorG. Rust, Alistairen_US
dc.contributor.authorvan der Weyden, Louiseen_US
dc.contributor.authorKristiansen, Glenen_US
dc.contributor.authorLi, Allenen_US
dc.contributor.authorL. Sarver, Aaronen_US
dc.contributor.authorA. T. Silverstein, Kevinen_US
dc.contributor.authorGrutzmann, Roberten_US
dc.contributor.authorAust, Danielaen_US
dc.contributor.authorRummele, Petraen_US
dc.contributor.authorKnosel, Thomasen_US
dc.contributor.authorHerd, Colinen_US
dc.contributor.authorL. Stemple, Dereken_US
dc.contributor.authorKettleborough, Rossen_US
dc.contributor.authorA. Brosnan, Jacquelineen_US
dc.contributor.authorLi, Angen_US
dc.contributor.authorMorgan, Richarden_US
dc.contributor.authorKnight, Spenceren_US
dc.contributor.authorYu, Junen_US
dc.contributor.authorStegeman, Shaneen_US
dc.contributor.authorS. Collier, Laraen_US
dc.contributor.authorJ. ten Hoeve, Jelleen_US
dc.contributor.authorRidder, Jeroenen_US
dc.contributor.authorP. Klein, Alisonen_US
dc.contributor.authorGoggins, Michaelen_US
dc.contributor.authorH. Hruban, Ralphen_US
dc.contributor.authorK. Chang, Daviden_US
dc.contributor.authorV. Biankin, Andrewen_US
dc.contributor.authorWood, Stephenen_US
dc.contributor.authoral, eten_US
dc.description.abstractPancreatic 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.en_US
dc.publisherNature Publishing Groupen_US
dc.publisher.placeUnited Kingdomen_US
dc.subject.fieldofresearchMolecular Targetsen_US
dc.titleThe deubiquitinase USP9X suppresses pancreatic ductal adenocarcinomaen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.hasfulltextNo Full Text

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