The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.


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-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(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.


Biankin AV, Johns AL, Mawson A, Chang DK, Brancato MA, Rowe SJ, Simpson SL, Martyn-Smith M, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead R, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink J, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Blankin AV, Asghari R, Merrett ND, Chang DK, Pavey DA, Das A, Cosman PH, Ismail K, O’Connor C, Lam VW, McLeod D, Pleass HC, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford L, Texler M, Forrest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Feeney K, Zeps N, Beilin M, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O’Rourke TJ, Chiang A, Fawcet JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Scarlett CJ, Kaplan W, Scarpa A.