Journal Article

Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells

Dubash, Taronish D., Anchang, Benedikt, Ball, Claudia R., Metzig, Marie, Glimm, Hanno, Moffa, Giusi, Hundsrucker, Christian, Spang, Rainer, Voloshanenko, Oksana, Demir, Kubilay, Boehm, Christina, Erdmann, Gerrit, Augustin, Iris, Sandmann, Thomas, Leible, Svenja, Kerr, Grainne, Boutros, Michael

2013

Overview

Aberrant regulation of the Wnt/β-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or β-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or β-catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind β-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or β-catenin depend on Wnt ligands and their secretion for a sufficient level of β-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls. Activating mutations in the Wnt signalling pathway are associated with colon cancer. Here the authors show that tumour cells carrying mutations in APC and β-catenin are still regulated by Wnt ligands, suggesting that Wnt secretion and receptor signalling remains important to control downstream signalling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 631/67/1504/1885/1393 / 631/80/86 / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Adenomatous Polyposis Coli Protein - genetics / Adenomatous Polyposis Coli Protein - metabolism / Animals / beta Catenin - genetics / beta Catenin - metabolism / Cell Line, Tumor / Cell Proliferation / Colon - metabolism / Colon - pathology / Colonic Neoplasms - genetics / Colonic Neoplasms - metabolism / Colonic Neoplasms - pathology / Colorectal carcinoma / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Mice / Mice, Inbred NOD / multidisciplinary / Mutation / Neoplasm Transplantation / Receptor, EphB2 - genetics / Receptor, EphB2 - metabolism / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Wnt3 Protein - genetics / Wnt3 Protein - metabolism