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Cancer Cell. 2015 Apr 13;27(4):561-73. doi: 10.1016/j.ccell.2015.02.014. Epub 2015 Apr 2.

Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis.

Author information

  • 1Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
  • 2Centre 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.
  • 3Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
  • 4Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany.
  • 5German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
  • 6German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; TAVARLIN AG, Biotechpark Pfungstadt, Reißstraße 1a, 64319 Pfungstadt, Germany.
  • 7Department of Histopathology, Imperial College London, Du Cane Road, London W12 0NN, UK.
  • 8Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
  • 9Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
  • 10Department of Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
  • 11Department 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.
  • 12Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
  • 132nd Department of Pathology, Semmelweis University Budapest, Ulloi ut 93, 1091 Budapest, Hungary.
  • 14Department 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.
  • 15Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
  • 16Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
  • 17Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany.
  • 18Division 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.
  • 19Centre 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.

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

PMID:
25843002
[PubMed - indexed for MEDLINE]
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