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Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations (1-4) in addition to numerous lower frequency genetic events of uncertain significance (5). Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis (6,7) in a mouse model of pancreatic ductal preneoplasia (8) to identify genes that cooperate with oncogenic [Kras.sup.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 (9), 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 [Kras.sup.G12D] 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., The biological sequelae of PDA has been partially attributed to frequent and well characterized mutations in KRAS (>90%), CDKN2A (>90%), TP53 (70%) and SMAD4 (55%) (1-4). Recent genomewide analyses have [...]