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

Silvia von Karstedt; Annalisa Conti; Max Nobis; Antonella Montinaro; Torsten Hartwig; Johannes Lemke; Karen Legler; Franka Annewanter; Andrew D Campbell; Lucia Taraborrelli; Anne Grosse-Wilde; Johannes F Coy; Mona A El-Bahrawy; Frank Bergmann; Ronald Koschny; Jens Werner; Tom M Ganten; Thomas Schweiger; Konrad Hoetzenecker; Istvan Kenessey; Balazs Hegedüs; Michael Bergmann; Charlotte Hauser; Jan-Hendrik Egberts; Thomas Becker; Christoph Röcken; Holger Kalthoff; Anna Trauzold; Kurt I Anderson; Owen J Sansom; Henning Walczak

doi:10.1016/j.ccell.2015.02.014

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

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

Authors

Silvia von Karstedt¹, Annalisa Conti², Max Nobis³, Antonella Montinaro¹, Torsten Hartwig¹, Johannes Lemke¹, Karen Legler⁴, Franka Annewanter⁴, Andrew D Campbell³, Lucia Taraborrelli¹, Anne Grosse-Wilde⁵, Johannes F Coy⁶, Mona A El-Bahrawy⁷, Frank Bergmann⁸, Ronald Koschny⁹, Jens Werner¹⁰, Tom M Ganten⁹, Thomas Schweiger¹¹, Konrad Hoetzenecker¹², Istvan Kenessey¹³, Balazs Hegedüs¹⁴, Michael Bergmann¹⁵, Charlotte Hauser¹⁶, Jan-Hendrik Egberts¹⁶, Thomas Becker¹⁶, Christoph Röcken¹⁷, Holger Kalthoff⁴, Anna Trauzold¹⁸, Kurt I Anderson³, Owen J Sansom³, Henning Walczak¹⁹

Affiliations

¹ Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
² 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.
³ Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
⁴ Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany.
⁵ German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
⁶ German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; TAVARLIN AG, Biotechpark Pfungstadt, Reißstraße 1a, 64319 Pfungstadt, Germany.
⁷ Department of Histopathology, Imperial College London, Du Cane Road, London W12 0NN, UK.
⁸ Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
⁹ Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
¹⁰ Department of Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
¹¹ 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.
¹² Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
¹³ 2nd Department of Pathology, Semmelweis University Budapest, Ulloi ut 93, 1091 Budapest, Hungary.
¹⁴ 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.
¹⁵ Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
¹⁶ Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
¹⁷ Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany.
¹⁸ 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.
¹⁹ Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism*
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Cell Proliferation / genetics
Disease Progression
Female
Humans
Male
Mice
Mice, Inbred C57BL
Mice, SCID
Models, Biological
Neoplasm Invasiveness / genetics
Prognosis
Proto-Oncogene Proteins p21(ras) / genetics*
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand / physiology*

Substances

Receptors, TNF-Related Apoptosis-Inducing Ligand
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding