Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis

von Karstedt, Silvia and Conti, Annalisa and Nobis, Max and Montinaro, Antonella and Hartwig, Torsten and Lemke, Johannes and Legler, Karen and Annewanter, Franka and Campbell, Andrew D. and Taraborrelli, Lucia and Grosse-Wilde, Anne and Coy, Johannes F. and El-Bahrawy, Mona A. and Bergmann, Frank and Koschny, Ronald and Werner, Jens and Ganten, Tom M. and Schweiger, Thomas and Hoetzenecker, Konrad and Kenessey, Istvan and Hegedüs, Balazs and Bergmann, Michael and Hauser, Charlotte and Egberts, Jan-Hendrik and Becker, Thomas and Röcken, Christoph and Kalthoff, Holger and Trauzold, Anna and Anderson, Kurt I. and Sansom, Owen J. and Walczak, Henning (2015) Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis. Cancer Cell, 27 (4). pp. 561-573. ISSN 15356108

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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-ex- pressed 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 inva- sion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph ves- sels and with shortened metastasis-free survival of KRAS- mutated colorectal cancer patients.

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