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

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-Seq analysis demonstrated downregulation of STAT3 and Wnt pathway components. Since EGF-R on myeloid cells, but not on intestinal epithelial cells is required for intestinal cancer and IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally inhibited in IL-6 -/- 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 ß-catenin dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer, which could circumvent intrinsic and acquired resistance to EGF-R blockade. Overall design: RNA sequencing of tumor tissue and surrounding unaffected tissue of Apc Min/+ and Apc Min/+ ::ADAM17 ex/ex

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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