title: Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis.
abstract: Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: von Karstedt
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK; Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Conti
authors.affiliation: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Nobis
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Montinaro
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hartwig
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Lemke
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Legler
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany.
authors.forename: Franka
authors.initials: F
authors.lastname: Annewanter
authors.affiliation: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Taraborrelli
authors.affiliation: German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Grosse-Wilde
authors.affiliation: German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; TAVARLIN AG, Biotechpark Pfungstadt, Reißstraße 1a, 64319 Pfungstadt, Germany.
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Coy
authors.affiliation: Department of Histopathology, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Mona A
authors.initials: MA
authors.lastname: El-Bahrawy
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Koschny
authors.affiliation: Department of Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schweiger
authors.affiliation: Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Konrad
authors.initials: K
authors.lastname: Hoetzenecker
authors.affiliation: 2nd Department of Pathology, Semmelweis University Budapest, Ulloi ut 93, 1091 Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Kenessey
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedüs
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Bergmann
authors.affiliation: Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.affiliation: Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.affiliation: Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany; Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Trauzold
authors.affiliation: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.affiliation: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: h.walczak@ucl.ac.uk.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000502:physiology*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
references.citation: Cancer Res. 1999 Jun 15;59(12):2770-5
references.pmid: 10383128
references.citation: J Clin Invest. 1999 Jul;104(2):155-62
references.pmid: 10411544
references.citation: J Natl Cancer Inst. 1999 Nov 17;91(22):1922-32
references.pmid: 10564676
references.citation: Immunity. 2000 Jun;12(6):599-609
references.pmid: 10894160
references.citation: Immunity. 2000 Jun;12(6):611-20
references.pmid: 10894161
references.citation: Science. 2000 Oct 13;290(5490):333-7
references.pmid: 11030651
references.citation: Cancer Lett. 2001 Feb 10;163(1):71-81
references.pmid: 11163110
references.citation: J Biol Chem. 2001 Sep 14;276(37):34743-52
references.pmid: 11461927
references.citation: J Biol Chem. 2001 Dec 7;276(49):46639-46
references.pmid: 11583996
references.citation: Genes Dev. 2001 Dec 15;15(24):3243-8
references.pmid: 11751630
references.citation: J Immunol. 2002 Feb 1;168(3):1356-61
references.pmid: 11801676
references.citation: Nat Cell Biol. 2002 Aug;4(8):621-5
references.pmid: 12134164
references.citation: Annu Rev Genomics Hum Genet. 2002;3:101-28
references.pmid: 12142355
references.citation: Cancer Cell. 2002 Jul;2(1):25-8
references.pmid: 12150822
references.citation: Mol Cell Biol. 2002 Sep;22(18):6582-91
references.pmid: 12192056
references.citation: EMBO J. 2002 Sep 2;21(17):4520-30
references.pmid: 12198154
references.citation: Am J Med Genet. 2002 Oct 30;115(3):183-8
references.pmid: 12407699
references.citation: Oncogene. 2003 Jun 19;22(25):3842-52
references.pmid: 12813457
references.citation: Clin Cancer Res. 2003 Aug 15;9(9):3397-405
references.pmid: 12960128
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: Cancer Cell. 2005 May;7(5):469-83
references.pmid: 15894267
references.citation: Cell Res. 2005 Jun;15(6):430-8
references.pmid: 15987601
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Jan;290(1):G129-36
references.pmid: 16166346
references.citation: J Biol Chem. 2005 Dec 9;280(49):40599-608
references.pmid: 16227629
references.citation: Oncogene. 2006 Nov 30;25(56):7434-9
references.pmid: 16751802
references.citation: J Urol. 2007 Jan;177(1):359-64
references.pmid: 17162091
references.citation: Cell. 2007 Jun 1;129(5):957-68
references.pmid: 17540175
references.citation: Clin Cancer Res. 2007 Jun 1;13(11):3403-12
references.pmid: 17545549
references.citation: Cancer Res. 2007 Sep 1;67(17):8089-94
references.pmid: 17804720
references.citation: J Clin Invest. 2008 Jan;118(1):111-23
references.pmid: 18079962
references.citation: J Clin Invest. 2008 Jan;118(1):100-10
references.pmid: 18079967
references.citation: Lung Cancer. 2008 Jun;60(3):355-65
references.pmid: 18093694
references.citation: Cell Death Differ. 2008 Apr;15(4):762-72
references.pmid: 18202702
references.citation: Cancer Res. 2008 Mar 1;68(5):1443-50
references.pmid: 18316608
references.citation: Nat Rev Mol Cell Biol. 2008 Sep;9(9):690-701
references.pmid: 18719708
references.citation: Cell. 2008 Oct 31;135(3):510-23
references.pmid: 18984162
references.citation: Nat Med. 2008 Dec;14(12):1351-6
references.pmid: 19029981
references.citation: Nat Med. 2008 Dec;14(12):1315-6
references.pmid: 19057554
references.citation: Clin Cancer Res. 2009 Jan 15;15(2):650-9
references.pmid: 19147771
references.citation: J Mol Med (Berl). 2009 Oct;87(10):995-1007
references.pmid: 19680616
references.citation: Nat Protoc. 2009;4(11):1623-31
references.pmid: 19834477
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):246-51
references.pmid: 20018721
references.citation: Nature. 2010 Mar 18;464(7287):436-40
references.pmid: 20173739
references.citation: Gastroenterology. 2010 Jun;138(7):2357-67
references.pmid: 20188103
references.citation: Curr Protoc Cell Biol. 2010 Mar;Chapter 14:Unit 14.11.1-26
references.pmid: 20235099
references.citation: J Mol Med (Berl). 2010 Jul;88(7):729-40
references.pmid: 20354842
references.citation: N Engl J Med. 2010 Apr 29;362(17):1605-17
references.pmid: 20427809
references.citation: PLoS One. 2010 Aug 16;5(8):e12178
references.pmid: 20808443
references.citation: Curr Opin Cell Biol. 2010 Oct;22(5):690-6
references.pmid: 20829016
references.citation: Gastroenterology. 2011 Aug;141(2):719-30, 730.e1-7
references.pmid: 21684285
references.citation: Future Med Chem. 2011 Oct;3(14):1787-808
references.pmid: 22004085
references.citation: Cancer Cell. 2012 Jan 17;21(1):105-20
references.pmid: 22264792
references.citation: J Cell Sci. 2012 Oct 1;125(Pt 19):4651-61
references.pmid: 22797920
references.citation: Cancer Res. 2012 Nov 1;72(21):5576-87
references.pmid: 22964582
references.citation: Nat Cell Biol. 2012 Nov;14(11):1169-80
references.pmid: 23103911
references.citation: Nat Protoc. 2013 Mar;8(3):583-94
references.pmid: 23429719
references.citation: Cell Stem Cell. 2013 Jun 6;12(6):761-73
references.pmid: 23665120
references.citation: Cell. 2013 May 23;153(5):1050-63
references.pmid: 23706742
references.citation: J Cell Sci. 2013 Oct 15;126(Pt 20):4572-88
references.pmid: 23902686
references.citation: Gastroenterology. 2014 Jan;146(1):278-90
references.pmid: 24120475
references.citation: Cancer Cell. 2013 Nov 11;24(5):617-30
references.pmid: 24229709
references.citation: Nature. 2013 Nov 28;503(7477):548-51
references.pmid: 24256730
references.citation: Cell Rep. 2014 Mar 27;6(6):1153-1164
references.pmid: 24630994
references.citation: Cell Death Differ. 2014 Sep;21(9):1350-64
references.pmid: 24948009
references.citation: Cancer Res. 1989 Sep 1;49(17):4682-9
references.pmid: 2547513
references.citation: Nature. 1984 Feb 16-22;307(5952):658-60
references.pmid: 6694757
references.citation: Science. 1993 Apr 2;260(5104):85-8
references.pmid: 8465203
references.citation: Immunity. 1997 Dec;7(6):813-20
references.pmid: 9430226
references.citation: Science. 1998 Jan 23;279(5350):560-3
references.pmid: 9438849
references.citation: Nat Med. 1999 Feb;5(2):157-63
references.pmid: 9930862