ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling

Stefanie Schmidt; Neele Schumacher; Jeanette Schwarz; Simone Tangermann; Lukas Kenner; Michaela Schlederer; Maria Sibilia; Markus Linder; Annelore Altendorf-Hofmann; Thomas Knösel; Elisabeth S. Gruber; Georg Oberhuber; Julia Bolik; Ateequr Rehman; Anupam Sinha; Juliane Lokau; Philipp Arnold; Anne Sophie Cabron; Friederike Zunke; Christoph Becker-Pauly; Adele Preaudet; Paul Nguyen; Jennifer Huynh; Shoukat Afshar-Sterle; Ashwini L. Chand; Jürgen Westermann; Peter J. Dempsey; Christoph Garbers; Dirk Schmidt-Arras; Philip Rosenstiel; Tracy Putoczki; Matthias Ernst; Stefan Rose-John

doi:10.1084/jem.20171696

ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling

Stefanie Schmidt, Neele Schumacher, Jeanette Schwarz, Simone Tangermann, Lukas Kenner, Michaela Schlederer, Maria Sibilia, Markus Linder, Annelore Altendorf-Hofmann, Thomas Knösel, Elisabeth S. Gruber, Georg Oberhuber, Julia Bolik, Ateequr Rehman, Anupam Sinha, Juliane Lokau, Philipp Arnold, Anne Sophie Cabron, Friederike Zunke, Christoph Becker-PaulyAdele Preaudet, Paul Nguyen, Jennifer Huynh, Shoukat Afshar-Sterle, Ashwini L. Chand, Jürgen Westermann, Peter J. Dempsey, Christoph Garbers, Dirk Schmidt-Arras, Philip Rosenstiel, Tracy Putoczki, Matthias Ernst, Stefan Rose-John^*

^*Corresponding author for this work

Institute of Anatomy

69 Citations (Scopus)

Abstract

Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated downregulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6 ^-/- mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.

Original language	English
Journal	Journal of Experimental Medicine
Volume	215
Issue number	4
Pages (from-to)	1205-1225
Number of pages	21
ISSN	0022-1007
DOIs	https://doi.org/10.1084/jem.20171696
Publication status	Published - 01.04.2018

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Schmidt, S., Schumacher, N., Schwarz, J., Tangermann, S., Kenner, L., Schlederer, M., Sibilia, M., Linder, M., Altendorf-Hofmann, A., Knösel, T., Gruber, E. S., Oberhuber, G., Bolik, J., Rehman, A., Sinha, A., Lokau, J., Arnold, P., Cabron, A. S., Zunke, F., ... Rose-John, S. (2018). ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling. Journal of Experimental Medicine, 215(4), 1205-1225. https://doi.org/10.1084/jem.20171696

@article{79bd3d912d9e43e589762c79a8eda423,

title = "ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling",

abstract = " Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated downregulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6 -/- mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade. ",

author = "Stefanie Schmidt and Neele Schumacher and Jeanette Schwarz and Simone Tangermann and Lukas Kenner and Michaela Schlederer and Maria Sibilia and Markus Linder and Annelore Altendorf-Hofmann and Thomas Kn{\"o}sel and Gruber, \{Elisabeth S.\} and Georg Oberhuber and Julia Bolik and Ateequr Rehman and Anupam Sinha and Juliane Lokau and Philipp Arnold and Cabron, \{Anne Sophie\} and Friederike Zunke and Christoph Becker-Pauly and Adele Preaudet and Paul Nguyen and Jennifer Huynh and Shoukat Afshar-Sterle and Chand, \{Ashwini L.\} and J{\"u}rgen Westermann and Dempsey, \{Peter J.\} and Christoph Garbers and Dirk Schmidt-Arras and Philip Rosenstiel and Tracy Putoczki and Matthias Ernst and Stefan Rose-John",

year = "2018",

month = apr,

day = "1",

doi = "10.1084/jem.20171696",

language = "English",

volume = "215",

pages = "1205--1225",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

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Schmidt, S, Schumacher, N, Schwarz, J, Tangermann, S, Kenner, L, Schlederer, M, Sibilia, M, Linder, M, Altendorf-Hofmann, A, Knösel, T, Gruber, ES, Oberhuber, G, Bolik, J, Rehman, A, Sinha, A, Lokau, J, Arnold, P, Cabron, AS, Zunke, F, Becker-Pauly, C, Preaudet, A, Nguyen, P, Huynh, J, Afshar-Sterle, S, Chand, AL, Westermann, J, Dempsey, PJ, Garbers, C, Schmidt-Arras, D, Rosenstiel, P, Putoczki, T, Ernst, M & Rose-John, S 2018, 'ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling', Journal of Experimental Medicine, vol. 215, no. 4, pp. 1205-1225. https://doi.org/10.1084/jem.20171696

TY - JOUR

T1 - ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling

AU - Schmidt, Stefanie

AU - Schumacher, Neele

AU - Schwarz, Jeanette

AU - Tangermann, Simone

AU - Kenner, Lukas

AU - Schlederer, Michaela

AU - Sibilia, Maria

AU - Linder, Markus

AU - Altendorf-Hofmann, Annelore

AU - Knösel, Thomas

AU - Gruber, Elisabeth S.

AU - Oberhuber, Georg

AU - Bolik, Julia

AU - Rehman, Ateequr

AU - Sinha, Anupam

AU - Lokau, Juliane

AU - Arnold, Philipp

AU - Cabron, Anne Sophie

AU - Zunke, Friederike

AU - Becker-Pauly, Christoph

AU - Preaudet, Adele

AU - Nguyen, Paul

AU - Huynh, Jennifer

AU - Afshar-Sterle, Shoukat

AU - Chand, Ashwini L.

AU - Westermann, Jürgen

AU - Dempsey, Peter J.

AU - Garbers, Christoph

AU - Schmidt-Arras, Dirk

AU - Rosenstiel, Philip

AU - Putoczki, Tracy

AU - Ernst, Matthias

AU - Rose-John, Stefan

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated downregulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6 -/- mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.

AB - Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated downregulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6 -/- mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.

UR - https://www.scopus.com/pages/publications/85044827602

U2 - 10.1084/jem.20171696

DO - 10.1084/jem.20171696

M3 - Journal articles

C2 - 29472497

AN - SCOPUS:85044827602

SN - 0022-1007

VL - 215

SP - 1205

EP - 1225

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 4

ER -

ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling

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