Search

Your search keyword '"Johannes Betge"' showing total 14 results
Start Over Author "Johannes Betge" Publisher georg thieme verlag kg
14 results on '"Johannes Betge"'

3. MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Author

I Hinsenkamp, Gerrit Erdmann, Giulia Ambrosi, Bernd Hessling, Benedikt Rauscher, Matthias P. Ebert, Elke Burgermeister, Tianzuo Zhan, Leonhard Bamberg, Michael Boutros, Karin Müller-Decker, N Rindtorff, Anna Maxi Wandmacher, Johannes Betge, and Ragna S. Häussler

Subjects
Male, Proteomics, 0301 basic medicine, Carcinogenesis, Colorectal cancer, Biopsy, Cell Plasticity, General Physics and Astronomy, Mice, SCID, 02 engineering and technology, medicine.disease_cause, Mice, Mice, Inbred NOD, lcsh:Science, Wnt Signaling Pathway, Multidisciplinary, Cancer stem cells, High-throughput screening, Wnt signaling pathway, LGR5, 021001 nanoscience & nanotechnology, Gene Expression Regulation, Neoplastic, Intestines, Neoplastic Stem Cells, Female, Stem cell, Colorectal Neoplasms, 0210 nano-technology, Science, Adenomatous Polyposis Coli Protein, Down-Regulation, Antineoplastic Agents, Biology, Article, Morphogen signalling, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Downregulation and upregulation, Cancer stem cell, Cell Line, Tumor, AXIN1, medicine, Animals, Humans, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase Kinases, HEK 293 cells, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, ras Proteins, Cancer research, lcsh:Q, CRISPR-Cas Systems
Abstract

In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition., Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results