MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
| Autor: | 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, Ragna S. Häussler |
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| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019) Nature Communications |
| ISSN: | 1439-7803 |
| DOI: | 10.1055/s-0039-1695401 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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