Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model
Bahar Degirmenci,
Cansu Dincer,
Habibe Cansu Demirel,
Linda Berkova,
Andreas E. Moor,
Abdullah Kahraman,
George Hausmann,
Michel Aguet,
Nurcan Tuncbag,
Tomas Valenta,
Konrad Basler
Affiliations
Bahar Degirmenci
Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse. 190, CH-8057 Zurich, Switzerland; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; National Nanotechnology Center, Bilkent University, Ankara, Turkey
Cansu Dincer
Graduate School of Informatics, Department of Health Informatics, METU, Ankara, Turkey
Habibe Cansu Demirel
Graduate School of Informatics, Department of Health Informatics, METU, Ankara, Turkey
Linda Berkova
Institute of Molecular Genetics of the ASCR, v. v. i., Vídeňská 1083142 20, Prague 4, Czech Republic
Andreas E. Moor
Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland; Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
Abdullah Kahraman
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
George Hausmann
Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse. 190, CH-8057 Zurich, Switzerland
Michel Aguet
Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland
Nurcan Tuncbag
Graduate School of Informatics, Department of Health Informatics, METU, Ankara, Turkey
Tomas Valenta
Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse. 190, CH-8057 Zurich, Switzerland; Institute of Molecular Genetics of the ASCR, v. v. i., Vídeňská 1083142 20, Prague 4, Czech Republic; Corresponding author
Konrad Basler
Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse. 190, CH-8057 Zurich, Switzerland; Corresponding author
Summary: Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.
