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

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

Fondazione IRCCS Istituto Nazionale dei Tumori

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	561-573
Number of pages	13
Journal	Cancer Cell
Volume	27
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2015.02.014
Publication status	Published - Apr 13 2015

ASJC Scopus subject areas

Cancer Research
Cell Biology
Oncology
Medicine(all)

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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

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

In: Cancer Cell, Vol. 27, No. 4, 13.04.2015, p. 561-573.

Research output: Contribution to journal › Article › peer-review

von Karstedt, S, Conti, A, Nobis, M, Montinaro, A, Hartwig, T, Lemke, J, Legler, K, Annewanter, F, Campbell, AD, Taraborrelli, L, Grosse-Wilde, A, Coy, JF, El-Bahrawy, MA, Bergmann, F, Koschny, R, Werner, J, Ganten, TM, Schweiger, T, Hoetzenecker, K, Kenessey, I, Hegedüs, B, Bergmann, M, Hauser, C, Egberts, JH, Becker, T, Röcken, C, Kalthoff, H, Trauzold, A, Anderson, KI, Sansom, OJ & Walczak, H 2015, 'Cancer cell-autonomous TRAIL-R signaling promotes KRAS-Driven cancer progression, invasion, and metastasis', Cancer Cell, vol. 27, no. 4, pp. 561-573. https://doi.org/10.1016/j.ccell.2015.02.014

von Karstedt, Silvia ; Conti, Annalisa ; Nobis, Max ; Montinaro, Antonella ; Hartwig, Torsten ; Lemke, Johannes ; Legler, Karen ; Annewanter, Franka ; Campbell, Andrew D. ; Taraborrelli, Lucia ; Grosse-Wilde, Anne ; Coy, Johannes F. ; El-Bahrawy, Mona A. ; Bergmann, Frank ; Koschny, Ronald ; Werner, Jens ; Ganten, Tom M. ; Schweiger, Thomas ; Hoetzenecker, Konrad ; Kenessey, Istvan ; Hegedüs, Balazs ; Bergmann, Michael ; Hauser, Charlotte ; Egberts, Jan Hendrik ; Becker, Thomas ; Röcken, Christoph ; Kalthoff, Holger ; Trauzold, Anna ; Anderson, Kurt I. ; Sansom, Owen J. ; Walczak, Henning. / Cancer cell-autonomous TRAIL-R signaling promotes KRAS-Driven cancer progression, invasion, and metastasis. In: Cancer Cell. 2015 ; Vol. 27, No. 4. pp. 561-573.

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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 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.",

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AU - von Karstedt, Silvia

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AU - Hartwig, Torsten

AU - Lemke, Johannes

AU - Legler, Karen

AU - Annewanter, Franka

AU - Campbell, Andrew D.

AU - Taraborrelli, Lucia

AU - Grosse-Wilde, Anne

AU - Coy, Johannes F.

AU - El-Bahrawy, Mona A.

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AU - Koschny, Ronald

AU - Werner, Jens

AU - Ganten, Tom M.

AU - Schweiger, Thomas

AU - Hoetzenecker, Konrad

AU - Kenessey, Istvan

AU - Hegedüs, Balazs

AU - Bergmann, Michael

AU - Hauser, Charlotte

AU - Egberts, Jan Hendrik

AU - Becker, Thomas

AU - Röcken, Christoph

AU - Kalthoff, Holger

AU - Trauzold, Anna

AU - Anderson, Kurt I.

AU - Sansom, Owen J.

AU - Walczak, Henning

PY - 2015/4/13

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N2 - 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.

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