Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis
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 a...
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| Vydané v: | Cancer cell Ročník 27; číslo 4; s. 561 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
13.04.2015
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| ISSN: | 1878-3686, 1878-3686 |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Sansom, Owen J Nobis, Max Egberts, Jan-Hendrik Campbell, Andrew D Hegedüs, Balazs Taraborrelli, Lucia Bergmann, Michael von Karstedt, Silvia Kenessey, Istvan Becker, Thomas Lemke, Johannes Montinaro, Antonella Anderson, Kurt I Koschny, Ronald Schweiger, Thomas Ganten, Tom M Grosse-Wilde, Anne Walczak, Henning El-Bahrawy, Mona A Kalthoff, Holger Legler, Karen Conti, Annalisa Werner, Jens Hartwig, Torsten Coy, Johannes F Röcken, Christoph Annewanter, Franka Bergmann, Frank Hoetzenecker, Konrad Trauzold, Anna Hauser, Charlotte |
| Author_xml | – sequence: 1 givenname: Silvia surname: von Karstedt fullname: von Karstedt, Silvia organization: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK – sequence: 2 givenname: Annalisa surname: Conti fullname: Conti, Annalisa organization: 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 – sequence: 3 givenname: Max surname: Nobis fullname: Nobis, Max organization: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK – sequence: 4 givenname: Antonella surname: Montinaro fullname: Montinaro, Antonella organization: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK – sequence: 5 givenname: Torsten surname: Hartwig fullname: Hartwig, Torsten organization: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK – sequence: 6 givenname: Johannes surname: Lemke fullname: Lemke, Johannes organization: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK – sequence: 7 givenname: Karen surname: Legler fullname: Legler, Karen organization: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany – sequence: 8 givenname: Franka surname: Annewanter fullname: Annewanter, Franka organization: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany – sequence: 9 givenname: Andrew D surname: Campbell fullname: Campbell, Andrew D organization: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK – sequence: 10 givenname: Lucia surname: Taraborrelli fullname: Taraborrelli, Lucia organization: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK – sequence: 11 givenname: Anne surname: Grosse-Wilde fullname: Grosse-Wilde, Anne organization: German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA – sequence: 12 givenname: Johannes F surname: Coy fullname: Coy, Johannes F organization: German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; TAVARLIN AG, Biotechpark Pfungstadt, Reißstraße 1a, 64319 Pfungstadt, Germany – sequence: 13 givenname: Mona A surname: El-Bahrawy fullname: El-Bahrawy, Mona A organization: Department of Histopathology, Imperial College London, Du Cane Road, London W12 0NN, UK – sequence: 14 givenname: Frank surname: Bergmann fullname: Bergmann, Frank organization: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany – sequence: 15 givenname: Ronald surname: Koschny fullname: Koschny, Ronald organization: Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany – sequence: 16 givenname: Jens surname: Werner fullname: Werner, Jens organization: Department of Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany – sequence: 17 givenname: Tom M surname: Ganten fullname: Ganten, Tom M organization: Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany – sequence: 18 givenname: Thomas surname: Schweiger fullname: Schweiger, Thomas organization: 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 – sequence: 19 givenname: Konrad surname: Hoetzenecker fullname: Hoetzenecker, Konrad organization: Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria – sequence: 20 givenname: Istvan surname: Kenessey fullname: Kenessey, Istvan organization: 2nd Department of Pathology, Semmelweis University Budapest, Ulloi ut 93, 1091 Budapest, Hungary – sequence: 21 givenname: Balazs surname: Hegedüs fullname: Hegedüs, Balazs organization: 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 – sequence: 22 givenname: Michael surname: Bergmann fullname: Bergmann, Michael organization: Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria – sequence: 23 givenname: Charlotte surname: Hauser fullname: Hauser, Charlotte organization: Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany – sequence: 24 givenname: Jan-Hendrik surname: Egberts fullname: Egberts, Jan-Hendrik organization: Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany – sequence: 25 givenname: Thomas surname: Becker fullname: Becker, Thomas organization: Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany – sequence: 26 givenname: Christoph surname: Röcken fullname: Röcken, Christoph organization: Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany – sequence: 27 givenname: Holger surname: Kalthoff fullname: Kalthoff, Holger organization: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany – sequence: 28 givenname: Anna surname: Trauzold fullname: Trauzold, Anna organization: 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 – sequence: 29 givenname: Kurt I surname: Anderson fullname: Anderson, Kurt I organization: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK – sequence: 30 givenname: Owen J surname: Sansom fullname: Sansom, Owen J organization: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK – sequence: 31 givenname: Henning surname: Walczak fullname: Walczak, Henning email: h.walczak@ucl.ac.uk organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25843002$$D View this record in MEDLINE/PubMed |
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| Snippet | Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely... |
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| SubjectTerms | 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 |
| Title | Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis |
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