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

• DOI: 10.1084/jem.20171696
• Publication Date: 2018-02-22T15:36:17Z
• Authors: Stefanie Schmidt; Neele Schumacher; Jeanette Schwarz; Simone Tangermann; Lukas Kenner; Michaela Schlederer; Maria Sibilia; Markus Linder; Annelore Altendor...; Thomas Knösel; Elisabeth S. Gruber; Georg Oberhuber; Julia Bolik; Ateequr Rehman; Anupam Sinha; Juliane Lokau; Philipp Arnold; Anne-Sophie Cabron; Friederike Zunke; Christoph Becker-...; Adele Preaudet; Paul Nguyen; Jennifer Huynh; Shoukat Afshar-St...; Ashwini L. Chand; Jürgen Westermann; Peter J. Dempsey; Christoph Garbers; Dirk Schmidt-Arras; Philip Rosenstiel; Tracy Putoczki; Matthias Ernst; Stefan Rose-John
• Keywords: 0301 basic medicine; Carcinogenesis; 610; ADAM17 Protein; 03 medical and health sciences; Cell Line, Tumor; Intestinal Neoplasms; Intestine, Small; Animals; Humans; Neoplasm Metastasis; Research Articles; Neoplasm Staging; Cell Nucleus; Interleukin-6; Gastrointestinal Microbiome; 3. Good health; ErbB Receptors; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Organoids; Disease Models, Animal; Ki-67 Antigen; Adenomatous Polyposis Coli; Colorectal Neoplasms

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 down-regulation 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.