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 KenesseyBalazs Hegedüs, Michael Bergmann, Charlotte Hauser, Jan Hendrik Egberts, Thomas Becker, Christoph Röcken, Holger Kalthoff, Anna Trauzold, Kurt I. Anderson, Owen J. Sansom, Henning Walczak

Research output: Contribution to journalArticle

105 Citations (Scopus)

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 invivo 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.

Original languageEnglish
Pages (from-to)561-573
Number of pages13
JournalCancer Cell
Volume27
Issue number4
DOIs
Publication statusPublished - Apr 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    von Karstedt, S., Conti, A., Nobis, M., Montinaro, A., Hartwig, T., Lemke, J., Legler, K., Annewanter, F., Campbell, A. D., Taraborrelli, L., Grosse-Wilde, A., Coy, J. F., El-Bahrawy, M. A., Bergmann, F., Koschny, R., Werner, J., Ganten, T. M., Schweiger, T., Hoetzenecker, K., ... Walczak, H. (2015). Cancer cell-autonomous TRAIL-R signaling promotes KRAS-Driven cancer progression, invasion, and metastasis. Cancer Cell, 27(4), 561-573. https://doi.org/10.1016/j.ccell.2015.02.014