title: Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling.
abstract: Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Susann
authors.initials: S
authors.lastname: Weissmueller
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Manchado
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Saborowski
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Elvin
authors.initials: E
authors.lastname: Wagenblast
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Davis
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Pfister
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kitzing
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technical University of Dresden, 01062 Dresden, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Aust
authors.affiliation: The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540, USA.
authors.forename: Elke K
authors.initials: EK
authors.lastname: Markert
authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Santa Lucia 4072, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 1BD, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technical University of Dresden, 01062 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney NSW 2010, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 1BD, UK.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D020797:Receptor, Platelet-Derived Growth Factor beta
references.citation: Mol Cell Biol. 2001 Mar;21(5):1874-87
references.pmid: 11238924
references.citation: Genes Dev. 2009 Jun 1;23(11):1364-77
references.pmid: 19487575
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10
references.pmid: 16381825
references.citation: Cancer Cell. 2005 May;7(5):469-83
references.pmid: 15894267
references.citation: Nature. 2010 Oct 21;467(7318):986-90
references.pmid: 20962848
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):246-51
references.pmid: 20018721
references.citation: Blood. 2003 Jun 15;101(12):5010-3
references.pmid: 12595307
references.citation: Oncogene. 2014 Mar 20;33(12):1601-8
references.pmid: 23584479
references.citation: Oncogene. 2007 Apr 2;26(15):2220-5
references.pmid: 17401431
references.citation: Oncogene. 2013 Jul 4;32(27):3286-95
references.pmid: 22847613
references.citation: Expert Opin Ther Pat. 2010 Jul;20(7):885-97
references.pmid: 20509775
references.citation: Adv Cancer Res. 2007;97:1-23
references.pmid: 17419939
references.citation: J Clin Oncol. 2012 Oct 10;30(29):3648-50
references.pmid: 22965952
references.citation: Oncogene. 2013 Jun 13;32(24):2992-3000
references.pmid: 22797073
references.citation: J Biol Chem. 2005 Dec 23;280(51):42242-51
references.pmid: 16251183
references.citation: Nucleic Acids Res. 1998 Aug 15;26(16):3800-5
references.pmid: 9685499
references.citation: Eur J Biochem. 1997 May 15;246(1):142-6
references.pmid: 9210476
references.citation: Nat Rev Cancer. 2009 Oct;9(10):749-58
references.pmid: 19776744
references.citation: PLoS One. 2013 Jun 21;8(6):e67581
references.pmid: 23805317
references.citation: Biochem Biophys Res Commun. 1995 May 5;210(1):165-73
references.pmid: 7741738
references.citation: Cell. 2012 Jan 20;148(1-2):244-58
references.pmid: 22265415
references.citation: J Biol Chem. 2002 Oct 18;277(42):39769-76
references.pmid: 12167641
references.citation: Cell. 2009 Dec 24;139(7):1327-41
references.pmid: 20064378
references.citation: Genes Dev. 2012 Jun 15;26(12):1268-86
references.pmid: 22713868
references.citation: Cancer Cell. 2003 May;3(5):439-43
references.pmid: 12781361
references.citation: Cell Death Differ. 2013 Jul;20(7):898-909
references.pmid: 23538418
references.citation: Cancer Cell. 2006 Sep;10(3):191-202
references.pmid: 16959611
references.citation: Cell. 2004 Dec 17;119(6):847-60
references.pmid: 15607980
references.citation: J Clin Oncol. 2009 Nov 1;27(31):5262-9
references.pmid: 19738123
references.citation: Cell. 2004 Dec 17;119(6):861-72
references.pmid: 15607981
references.citation: Cancer. 1995 Mar 15;75(6):1327-38
references.pmid: 7882283
references.citation: Lancet. 2004 Mar 27;363(9414):1049-57
references.pmid: 15051286
references.citation: Nat Rev Cancer. 2001 Dec;1(3):233-40
references.pmid: 11902578
references.citation: Mol Aspects Med. 2013 Apr-Jun;34(2-3):270-87
references.pmid: 23506870
references.citation: Cancer Cell. 2004 Oct;6(4):333-45
references.pmid: 15488757
references.citation: Cell. 2009 Apr 3;137(1):87-98
references.pmid: 19345189
references.citation: BMC Cancer. 2013 Feb 27;13:95
references.pmid: 23446043
references.citation: Mol Cell Biol. 2011 Nov;31(22):4464-81
references.pmid: 21930790
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: Br J Cancer. 2013 Sep 17;109(6):1408-13
references.pmid: 23963139
references.citation: Oncogene. 2007 May 17;26(23):3329-37
references.pmid: 17130833
references.citation: Science. 2008 Sep 26;321(5897):1801-6
references.pmid: 18772397