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  Oncogenic ß-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids

Riemer, P., Rydenfelt, M., Marks, M., van Eunen, K., Thedieck, K., Herrmann, B. G., et al. (2017). Oncogenic ß-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids. The Journal of Cell Biology: JCB, 216(6), 1567-1577. doi:10.1083/jcb.201610058.

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 Creators:
Riemer, Pamela1, 2, Author
Rydenfelt, Mattias 3, Author
Marks, Matthias4, Author              
van Eunen, Karen5, Author
Thedieck, Kathrin 5, Author
Herrmann, Bernhard G.4, Author              
Blüthgen, Nils1, 3, Author
Sers, Christine1, 2, Author
Morkel, Markus1, Author
Affiliations:
1Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany, ou_persistent22              
2German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany, ou_persistent22              
3Integrative Research Institute Life Sciences, Humboldt University Berlin, 10099 Berlin, Germany, ou_persistent22              
4Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
5Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, 9713 GZ Groningen, Netherlands, ou_persistent22              

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 Abstract: Colorectal cancer is driven by cooperating oncogenic mutations. In this study, we use organotypic cultures derived from transgenic mice inducibly expressing oncogenic β-catenin and/or PIK3CAH1047R to follow sequential changes in cancer-related signaling networks, intestinal cell metabolism, and physiology in a three-dimensional environment mimicking tissue architecture. Activation of β-catenin alone results in the formation of highly clonogenic cells that are nonmotile and prone to undergo apoptosis. In contrast, coexpression of stabilized β-catenin and PIK3CAH1047R gives rise to intestinal cells that are apoptosis-resistant, proliferative, stem cell–like, and motile. Systematic inhibitor treatments of organoids followed by quantitative phenotyping and phosphoprotein analyses uncover key changes in the signaling network topology of intestinal cells after induction of stabilized β-catenin and PIK3CAH1047R. We find that survival and motility of organoid cells are associated with 4EBP1 and AKT phosphorylation, respectively. Our work defines phenotypes, signaling network states, and vulnerabilities of transgenic intestinal organoids as a novel approach to understanding oncogene activities and guiding the development of targeted therapies.

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Language(s): eng - English
 Dates: 2017-04-252017-06-05
 Publication Status: Published in print
 Pages: 11
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1083/jcb.201610058
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Title: The Journal of Cell Biology : JCB
  Other : J. Cell Biol.
Source Genre: Journal
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Publ. Info: New York, NY : Rockefeller Institute Press
Pages: - Volume / Issue: 216 (6) Sequence Number: - Start / End Page: 1567 - 1577 Identifier: ISSN: 0021-9525
CoNE: https://pure.mpg.de/cone/journals/resource/991042742946024