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

The Journal of Experimental Medicine
Stefanie SchmidtStefan Rose-John

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 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.

References

Jan 1, 1981·Laboratory Animals·C Moolenbeek, E J Ruitenberg
Jun 1, 1994·The Biochemical Journal·S Rose-John, P C Heinrich
Oct 18, 1996·Cell·K W Kinzler, B Vogelstein
Dec 20, 2000·European Journal of Biochemistry·T JostockS Rose-John
Jan 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·Reade B RobertsDavid W Threadgill
Mar 4, 2003·Gastroenterology·Gregory P BoivinRobert J Coffey
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Carl P Blobel
Oct 21, 2006·Cancer Science·Yasuhiro Yamada, Hideki Mori
Nov 15, 2007·Differentiation; Research in Biological Diversity·Maria SibiliaMartin Holcmann
Dec 7, 2007·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Kristen A BaltgalvisJames A Carson
Jun 10, 2008·Pathology, Research and Practice·Amy E McCartAndrew Silver
Oct 23, 2008·Nucleic Acids Research·Lars J JensenChristian von Mering
Jun 11, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Debby M E I HellebrekersManon van Engeland
Jul 1, 2009·The Journal of Experimental Medicine·Geethanjali PickertChristoph Becker
Feb 5, 2010·Bioinformatics·Donovan H Parks, Robert G Beiko
Apr 28, 2010·Gastroenterology·Janos TerzićMichael Karin
Jul 7, 2010·The Journal of Experimental Medicine·Athena ChalarisStefan Rose-John
Jan 12, 2011·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Nerbil KilicUdo Schumacher
Jan 22, 2011·Nature Reviews. Molecular Cell Biology·Roi Avraham, Yosef Yarden
Feb 8, 2011·Biochimica Et Biophysica Acta·Jürgen SchellerStefan Rose-John
Jul 15, 2011·Trends in Immunology·Jürgen SchellerStefan Rose-John
Sep 2, 2011·The Journal of Clinical Investigation·Simon A JonesStefan Rose-John
Sep 14, 2012·G3 : Genes - Genomes - Genetics·Andrew T KwonWyeth W Wasserman
Jun 19, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Martina E SpehlmannLars Eckmann
Aug 27, 2013·Nature Biotechnology·Morgan G I LangilleCurtis Huttenhower

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Citations

Nov 24, 2018·Biochemical Society Transactions·Mustafa Yassin TaherJohn Maher
Dec 27, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Serena QuartaMichaela Kress
Mar 6, 2019·EMBO Molecular Medicine·Mohamed I SaadBrendan J Jenkins
Nov 7, 2019·Cancers·Neele Schumacher, Stefan Rose-John
Jul 2, 2019·Carcinogenesis·Mohamed I SaadBrendan J Jenkins
Jun 25, 2018·Aging·Marie Kveiborg, Gary Thomas
Dec 24, 2018·Nature Reviews. Cancer·Jennifer HuynhMatthias Ernst
Aug 24, 2019·Cancers·Mohamed I SaadBrendan J Jenkins
Aug 31, 2020·F1000Research·Stefan Rose-John
Jul 24, 2020·International Journal of Molecular Sciences·Neele SchumacherDirk Schmidt-Arras
Nov 13, 2019·Seminars in Cancer Biology·Pathum S ThilakasiriAshwini L Chand
Dec 19, 2019·RNA Biology·Shengyun MaWendy Jia Men Huang
Feb 14, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Matteo CalligarisSimone Dario Scilabra
May 18, 2021·Frontiers in Oncology·Qun ZhaoXianjun Yu
Jun 5, 2021·Nature Reviews. Cancer·Daria BriukhovetskaSebastian Kobold
May 23, 2021·Cytokine·Stefan Rose-John
Jul 3, 2021·Diagnostics·Yanjun ZhouStefanie Maurer
Jul 7, 2021·Molecular Oncology·Oliver DrägerNicole Dünker
Aug 8, 2021·Journal of Clinical Medicine·Margherita SistoSabrina Lisi
Aug 20, 2021·Cytokine·Robert H JenkinsSimon A Jones
Oct 26, 2021·Frontiers in Molecular Biosciences·Antonin GellrichChristoph Becker-Pauly
Dec 18, 2021·The Journal of Experimental Medicine·Julia BolikDirk Schmidt-Arras

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Datasets Mentioned

BETA
GSE107759

Methods Mentioned

BETA
ELISA
PCR
laser capture microdissection
Laser
transgenic
protein assay
Assay

Software Mentioned

NIS
Mothur
PICRUSt
Cytoscape
LightCycler 480
Elements D
Bioconductor package
STAMP
oPossum
DeSeq2

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