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Nat Commun. 2014 Oct 8;5:5005. doi: 10.1038/ncomms6005.

Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut.

Author information

1
1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
2
1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
3
1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Cell and Tissue Imaging Facility, PICT-IBiSA, CNRS, UMR 144, Paris 75248, France.
4
1] Inserm U735, Hôpital René Huguenin, 92210 Saint-Cloud, France [2] Institut Curie, Hôpital René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France.
5
Institut Curie, Centre Hospitalier, Paris 75248, France.
6
1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR3215, Paris 75248, France [3] Inserm U934, Paris 75248, France.
7
Next-Generation Sequencing Platform, Institut Curie, Paris 75248, France.
8
1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR168, Paris 75248, France.

Abstract

Epithelial-to-mesenchymal transition-like (EMT-like) is a critical process allowing initiation of metastases during tumour progression. Here, to investigate its role in intestinal cancer, we combine computational network-based and experimental approaches to create a mouse model with high metastatic potential. Construction and analysis of this network map depicting molecular mechanisms of EMT regulation based on the literature suggests that Notch activation and p53 deletion have a synergistic effect in activating EMT-like processes. To confirm this prediction, we generate transgenic mice by conditionally activating the Notch1 receptor and deleting p53 in the digestive epithelium (NICD/p53(-/-)). These mice develop metastatic tumours with high penetrance. Using GFP lineage tracing, we identify single malignant cells with mesenchymal features in primary and metastatic tumours in vivo. The development of such a model that recapitulates the cellular features observed in invasive human colorectal tumours is appealing for innovative drug discovery.

PMID:
25295490
PMCID:
PMC4214431
DOI:
10.1038/ncomms6005
[Indexed for MEDLINE]
Free PMC Article

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