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 - http://www.scopus.com/inward/record.url?scp=85044827602&partnerID=8YFLogxK
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 -
