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J Cell Biol. 2017 Jun 5;216(6):1567-1577. doi: 10.1083/jcb.201610058. Epub 2017 Apr 25.

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

Author information

1
Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
2
German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
3
Integrative Research Institute Life Sciences, Humboldt University Berlin, 10099 Berlin, Germany.
4
Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
5
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, 9713 GZ Groningen, Netherlands.
6
Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany markus.morkel@charite.de.

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.

PMID:
28442534
PMCID:
PMC5461020
DOI:
10.1083/jcb.201610058
[Indexed for MEDLINE]
Free PMC Article

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