The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pedro A. Pérez-Mancera; Alistair G. Rust; Louise Van Der Weyden; Glen Kristiansen; Allen Li; Aaron L. Sarver; Kevin A T Silverstein; Robert Grützmann; Daniela Aust; Petra Rümmele; Thomas Knösel; Colin Herd; Derek L. Stemple; Ross Kettleborough; Jacqueline A. Brosnan; Ang Li; Richard Morgan; Spencer Knight; Jun Yu; Shane Stegeman; Lara S. Collier; Jelle J. Ten Hoeve; Jeroen De Ridder; Alison P. Klein; Michael Goggins; Ralph H. Hruban; David K. Chang; Andrew V Wessels Biankin; Sean M. Grimmond; Lodewyk F A Wessels; Stephen A. Wood; Christine A. Iacobuzio-Donahue; Christian Pilarsky; David A. Largaespada; David J. Adams; David A. Tuveson; Andrew V. Bienkin; Amber L. Johns; Amanda Mawson; David K. Cheng; 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; Sean M. Grimond; 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; Jaswinder S. Samra; Anthony J. Gill; Nick Pavlakis; Alex Guminski; Christopher Toon; Andrew V. Blankin; Ray Asghari; Neil D. Merrett; Darren A. Pavey; Amithabad Das; Peter H. Cosman; Kasim Ismail; Chelsie O'Connor; Vincent W. Lam; Duncan McLeod; Henry C. Pleass; Virginia James; James G. Kench; Caroline L. Cooper; David Joseph; Charbel Sandroussi; Michael Crawford; Michael Texler; Cindy Forrest; Andrew Laycock; Krishna P. Epari; Mo Ballal; David R. Fletcher; Sanjay Mukhedkar; Nigel A. Spry; Bastiaan Deboer; Ming Chai; Kynan Feeney; Nikolajs Zeps; Maria Beilin; Nam Q. Nguyen; Andrew R. Ruszkiewicz; Chris Worthley; Chuan P. Tan; Tamara Debrencini; John Chen; Mark E. Brooke-Smith; Virginia Papangelis; Henry Tang; Andrew P. Barbour; Andrew D. Clouston; Patrick Martin; Thomas J. O'Rourke; Amy Chiang; Jonathan W. Fawcett; Kellee Slater; Shinn Yeung; Michael Hatzifotis; Peter Hodgkinson; Christopher Christophi; Mehrdad Nikfarjam; Victorian Cancer Biobank; James R. Eshleman; Anirban Maitra; Richard D. Schulick; Christopher L. Wolfgang; Richard A. Morgan; Rita T. Lawlor; Stefania Beghelli; Vincenzo Corbo; Maria Scardoni; Claudio Bassi; Margaret A. Tempero

doi:10.1038/nature11114

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pedro A. Pérez-Mancera, Alistair G. Rust, Louise Van Der Weyden, Glen Kristiansen, Allen Li, Aaron L. Sarver, Kevin A T Silverstein, Robert Grützmann, Daniela Aust, Petra Rümmele, Thomas Knösel, Colin Herd, Derek L. Stemple, Ross Kettleborough, Jacqueline A. Brosnan, Ang Li, Richard Morgan, Spencer Knight, Jun Yu, Shane StegemanLara S. Collier, Jelle J. Ten Hoeve, Jeroen De Ridder, Alison P. Klein, Michael Goggins, Ralph H. Hruban, David K. Chang, Andrew V Wessels Biankin, Sean M. Grimmond, Lodewyk F A Wessels, Stephen A. Wood, Christine A. Iacobuzio-Donahue, Christian Pilarsky, David A. Largaespada, David J. Adams, David A. Tuveson, Andrew V. Bienkin, Amber L. Johns, Amanda Mawson, David K. Cheng, 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, Sean M. Grimond, 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, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Andrew V. Blankin, Ray Asghari, Neil D. Merrett, Darren A. Pavey, Amithabad Das, Peter H. Cosman, Kasim Ismail, Chelsie O'Connor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, Michael Texler, Cindy Forrest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan Deboer, Ming Chai, Kynan Feeney, Nikolajs Zeps, Maria Beilin, Nam Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O'Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Victorian Cancer Biobank, James R. Eshleman, Anirban Maitra, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero

Research output: Contribution to journal › Article › peer-review

276 Scopus citations

Abstract

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-22-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.

Original language	English (US)
Pages (from-to)	266-270
Number of pages	5
Journal	Nature
Volume	486
Issue number	7402
DOIs	https://doi.org/10.1038/nature11114
State	Published - Jun 14 2012

Bibliographical note

Funding Information:
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 SPOREgrant to D.A.T., D.A.L. andC.A.I.-D.; grants CA62924, CA128920 andCA106610 to C.A.I.-D.; P50CA62924 SPORE grantto 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. andthe APGIinvestigators are fundedbythe NationalHealthandMedical 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 Fundación Ibercaja (P.A.P.-M.).

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Pérez-Mancera, P. A., Rust, A. G., Van Der Weyden, L., Kristiansen, G., Li, A., Sarver, A. L., Silverstein, K. A. T., Grützmann, R., Aust, D., Rümmele, P., Knösel, T., Herd, C., Stemple, D. L., Kettleborough, R., Brosnan, J. A., Li, A., Morgan, R., Knight, S., Yu, J., ... Tempero, M. A. (2012). The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature, 486(7402), 266-270. https://doi.org/10.1038/nature11114

Pérez-Mancera, PA, Rust, AG, Van Der Weyden, L, Kristiansen, G, Li, A, Sarver, AL , Silverstein, KAT, Grützmann, R, Aust, D, Rümmele, P, Knösel, T, Herd, C, Stemple, DL, Kettleborough, R, Brosnan, JA, Li, A, Morgan, R, Knight, S, Yu, J, Stegeman, S, Collier, LS, Ten Hoeve, JJ, De Ridder, J, Klein, AP, Goggins, M, Hruban, RH, Chang, DK, Biankin, AVW, Grimmond, SM, Wessels, LFA, Wood, SA, Iacobuzio-Donahue, CA, Pilarsky, C, Largaespada, DA, Adams, DJ, Tuveson, DA, Bienkin, AV, Johns, AL, Mawson, A, Cheng, DK, Brancato, MAL, Rowe, SJ, Simpson, SL, Martyn-Smith, M, Chantrill, LA, Chin, VT, Chou, A, Cowley, MJ, Humphris, JL, Jones, MD, Scott Mead, R, Nagrial, AM, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Daly, RJ, Musgrove, EA, Sutherland, RL, Grimond, 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, Lynn 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, 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, M, 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, Fawcett, JW, Slater, K, Yeung, S, Hatzifotis, M, Hodgkinson, P, Christophi, C, Nikfarjam, M, Cancer Biobank, V, Eshleman, JR, Maitra, A, Schulick, RD, Wolfgang, CL, Morgan, RA, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C & Tempero, MA 2012, 'The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma', Nature, vol. 486, no. 7402, pp. 266-270. https://doi.org/10.1038/nature11114

@article{2eeb6122c89142a4bfa4fc50a0e81112,

title = "The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma",

abstract = "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-22-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.",

author = "P{\'e}rez-Mancera, {Pedro A.} and Rust, {Alistair G.} and {Van Der Weyden}, Louise and Glen Kristiansen and Allen Li and Sarver, {Aaron L.} and Silverstein, {Kevin A T} and Robert Gr{\"u}tzmann and Daniela Aust and Petra R{\"u}mmele and Thomas Kn{\"o}sel and Colin Herd and Stemple, {Derek L.} and Ross Kettleborough and Brosnan, {Jacqueline A.} and Ang Li and Richard Morgan and Spencer Knight and Jun Yu and Shane Stegeman and Collier, {Lara S.} and {Ten Hoeve}, {Jelle J.} and {De Ridder}, Jeroen and Klein, {Alison P.} and Michael Goggins and Hruban, {Ralph H.} and Chang, {David K.} and Biankin, {Andrew V Wessels} and Grimmond, {Sean M.} and Wessels, {Lodewyk F A} and Wood, {Stephen A.} and Iacobuzio-Donahue, {Christine A.} and Christian Pilarsky and Largaespada, {David A.} and Adams, {David J.} and Tuveson, {David A.} and Bienkin, {Andrew V.} and Johns, {Amber L.} and Amanda Mawson and Cheng, {David K.} and Brancato, {Mary Anne L} and Rowe, {Sarah J.} and Simpson, {Skye L.} and Mona Martyn-Smith and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Angela Chou and Cowley, {Mark J.} and Humphris, {Jeremy L.} and Jones, {Marc D.} and {Scott Mead}, R. and Nagrial, {Adnan M.} and Marina Pajic and Jessica Pettit and Mark Pinese and Ilse Rooman and Jianmin Wu and Daly, {Roger J.} and Musgrove, {Elizabeth A.} and Sutherland, {Robert L.} and Grimond, {Sean M.} and Nicola Waddell and Kassahn, {Karin S.} and Miller, {David K.} and Wilson, {Peter J.} and Patch, {Ann Marie} and Sarah Song and Ivon Harliwong and Senel Idrisoglu and Craig Nourse and Ehsan Nourbakhsh and Suzanne Manning and Shivangi Wani and Milena Gongora and Matthew Anderson and Oliver Holmes and Conrad Leonard and Darrin Taylor and Scott Wood and Christina Xu and Katia Nones and {Lynn Fink}, J. and Angelika Christ and Tim Bruxner and Nicole Cloonan and Felicity Newell and Pearson, {John V.} and Samra, {Jaswinder S.} and Gill, {Anthony J.} and Nick Pavlakis and Alex Guminski and Christopher Toon and Blankin, {Andrew V.} and Ray Asghari and Merrett, {Neil D.} and Pavey, {Darren A.} and Amithabad Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O'Connor and Lam, {Vincent W.} and Duncan McLeod and Pleass, {Henry C.} and Virginia James and Kench, {James G.} and Cooper, {Caroline L.} and David Joseph and Charbel Sandroussi and Michael Crawford and Michael Texler and Cindy Forrest and Andrew Laycock and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Spry, {Nigel A.} and Bastiaan Deboer and Ming Chai and Kynan Feeney and Nikolajs Zeps and Maria Beilin and Nguyen, {Nam Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and Tan, {Chuan P.} and Tamara Debrencini and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Henry Tang and Barbour, {Andrew P.} and Clouston, {Andrew D.} and Patrick Martin and O'Rourke, {Thomas J.} and Amy Chiang and Fawcett, {Jonathan W.} and Kellee Slater and Shinn Yeung and Michael Hatzifotis and Peter Hodgkinson and Christopher Christophi and Mehrdad Nikfarjam and {Cancer Biobank}, Victorian and Eshleman, {James R.} and Anirban Maitra and Schulick, {Richard D.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and Tempero, {Margaret A.}",

note = "Funding Information: 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{\textquoteright}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 SPOREgrant to D.A.T., D.A.L. andC.A.I.-D.; grants CA62924, CA128920 andCA106610 to C.A.I.-D.; P50CA62924 SPORE grantto 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. andthe APGIinvestigators are fundedbythe NationalHealthandMedical 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 Fundaci{\'o}n Ibercaja (P.A.P.-M.).",

year = "2012",

month = jun,

day = "14",

doi = "10.1038/nature11114",

language = "English (US)",

volume = "486",

pages = "266--270",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7402",

}

TY - JOUR

T1 - The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

AU - Pérez-Mancera, Pedro A.

AU - Rust, Alistair G.

AU - Van Der Weyden, Louise

AU - Kristiansen, Glen

AU - Li, Allen

AU - Sarver, Aaron L.

AU - Silverstein, Kevin A T

AU - Grützmann, Robert

AU - Aust, Daniela

AU - Rümmele, Petra

AU - Knösel, Thomas

AU - Herd, Colin

AU - Stemple, Derek L.

AU - Kettleborough, Ross

AU - Brosnan, Jacqueline A.

AU - Li, Ang

AU - Morgan, Richard

AU - Knight, Spencer

AU - Yu, Jun

AU - Stegeman, Shane

AU - Collier, Lara S.

AU - Ten Hoeve, Jelle J.

AU - De Ridder, Jeroen

AU - Klein, Alison P.

AU - Goggins, Michael

AU - Hruban, Ralph H.

AU - Chang, David K.

AU - Biankin, Andrew V Wessels

AU - Grimmond, Sean M.

AU - Wessels, Lodewyk F A

AU - Wood, Stephen A.

AU - Iacobuzio-Donahue, Christine A.

AU - Pilarsky, Christian

AU - Largaespada, David A.

AU - Adams, David J.

AU - Tuveson, David A.

AU - Bienkin, Andrew V.

AU - Johns, Amber L.

AU - Mawson, Amanda

AU - Cheng, David K.

AU - Brancato, Mary Anne L

AU - Rowe, Sarah J.

AU - Simpson, Skye L.

AU - Martyn-Smith, Mona

AU - Chantrill, Lorraine A.

AU - Chin, Venessa T.

AU - Chou, Angela

AU - Cowley, Mark J.

AU - Humphris, Jeremy L.

AU - Jones, Marc D.

AU - Scott Mead, R.

AU - Nagrial, Adnan M.

AU - Pajic, Marina

AU - Pettit, Jessica

AU - Pinese, Mark

AU - Rooman, Ilse

AU - Wu, Jianmin

AU - Daly, Roger J.

AU - Musgrove, Elizabeth A.

AU - Sutherland, Robert L.

AU - Grimond, Sean M.

AU - Waddell, Nicola

AU - Kassahn, Karin S.

AU - Miller, David K.

AU - Wilson, Peter J.

AU - Patch, Ann Marie

AU - Song, Sarah

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Manning, Suzanne

AU - Wani, Shivangi

AU - Gongora, Milena

AU - Anderson, Matthew

AU - Holmes, Oliver

AU - Leonard, Conrad

AU - Taylor, Darrin

AU - Wood, Scott

AU - Xu, Christina

AU - Nones, Katia

AU - Lynn Fink, J.

AU - Christ, Angelika

AU - Bruxner, Tim

AU - Cloonan, Nicole

AU - Newell, Felicity

AU - Pearson, John V.

AU - Samra, Jaswinder S.

AU - Gill, Anthony J.

AU - Pavlakis, Nick

AU - Guminski, Alex

AU - Toon, Christopher

AU - Blankin, Andrew V.

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - Pavey, Darren A.

AU - Das, Amithabad

AU - Cosman, Peter H.

AU - Ismail, Kasim

AU - O'Connor, Chelsie

AU - Lam, Vincent W.

AU - McLeod, Duncan

AU - Pleass, Henry C.

AU - James, Virginia

AU - Kench, James G.

AU - Cooper, Caroline L.

AU - Joseph, David

AU - Sandroussi, Charbel

AU - Crawford, Michael

AU - Texler, Michael

AU - Forrest, Cindy

AU - Laycock, Andrew

AU - Epari, Krishna P.

AU - Ballal, Mo

AU - Fletcher, David R.

AU - Mukhedkar, Sanjay

AU - Spry, Nigel A.

AU - Deboer, Bastiaan

AU - Chai, Ming

AU - Feeney, Kynan

AU - Zeps, Nikolajs

AU - Beilin, Maria

AU - Nguyen, Nam Q.

AU - Ruszkiewicz, Andrew R.

AU - Worthley, Chris

AU - Tan, Chuan P.

AU - Debrencini, Tamara

AU - Chen, John

AU - Brooke-Smith, Mark E.

AU - Papangelis, Virginia

AU - Tang, Henry

AU - Barbour, Andrew P.

AU - Clouston, Andrew D.

AU - Martin, Patrick

AU - O'Rourke, Thomas J.

AU - Chiang, Amy

AU - Fawcett, Jonathan W.

AU - Slater, Kellee

AU - Yeung, Shinn

AU - Hatzifotis, Michael

AU - Hodgkinson, Peter

AU - Christophi, Christopher

AU - Nikfarjam, Mehrdad

AU - Cancer Biobank, Victorian

AU - Eshleman, James R.

AU - Maitra, Anirban

AU - Schulick, Richard D.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Lawlor, Rita T.

AU - Beghelli, Stefania

AU - Corbo, Vincenzo

AU - Scardoni, Maria

AU - Bassi, Claudio

AU - Tempero, Margaret A.

N1 - Funding Information: 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 SPOREgrant to D.A.T., D.A.L. andC.A.I.-D.; grants CA62924, CA128920 andCA106610 to C.A.I.-D.; P50CA62924 SPORE grantto 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. andthe APGIinvestigators are fundedbythe NationalHealthandMedical 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 Fundación Ibercaja (P.A.P.-M.).

PY - 2012/6/14

Y1 - 2012/6/14

N2 - 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-22-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.

AB - 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-22-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.

UR - http://www.scopus.com/inward/record.url?scp=84861990162&partnerID=8YFLogxK

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U2 - 10.1038/nature11114

DO - 10.1038/nature11114

M3 - Article

C2 - 22699621

AN - SCOPUS:84861990162

SN - 0028-0836

VL - 486

SP - 266

EP - 270

JO - Nature

JF - Nature

IS - 7402

ER -

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

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