Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6005
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Funding
- Agence Nationale de le Recherche (investissements d'avenir) [ANR-10-EQPX-03, ANR10-INBS-09-08]
- Canceropole Ile-de-France
- Curie Institute Foundation
- Institut National du Cancer
- Ligue Nationale contre le Cancer Comite de Paris
- 'Projet Incitatif et Collaboratif: Computational Systems Biology Approach for Cancer' from Institut Curie
- Fondation pour la Recherche Medicale
- European Committee Oncodeath [037278]
- Marie Curie Fellowship (EuroCancer StemCell Training Network)
- La Ligue contre le cancer
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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.
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