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

Maia Chanrion (1) , Inna Kuperstein (2) , Cédric Barrière , Fatima El Marjou , David Cohen (3) , Danijela Vignjevic (4) , Lev Stimmer , Perrine Paul-Gilloteaux (4) , Ivan Bièche (5) , Silvina dos Reis Tavares , Giuseppe-Fulvio Boccia , Wulfran Cacheux (6) , Didier Meseure (7) , Silvia Fre , Loredana Martignetti , Patricia Legoix-Né (8) , Elodie Girard , Luc Fetler (9) , Emmanuel Barillot (2) , Daniel Louvard (4) , Andrei Zinovyev (10) , Sylvie Robine (4)

1 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier
2 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
3 ISIR - Institut des Systèmes Intelligents et de Robotique
4 CDC - Compartimentation et dynamique cellulaires
5 Facultés des sciences pharmaceutiques et biologiques
6 CRLCC René Huguenin - CRLCC René Huguenin
7 Platform of Investigative Pathology
8 Institut Curie [Paris]
9 PCC - Physico-Chimie-Curie
10 CURIE-BIOINFO - Service de Bioinformatique

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.

Domains: Life Sciences [q-bio]

Maia Chanrion, Inna Kuperstein, Cédric Barrière, Fatima El Marjou, David Cohen, et al.. Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. Nature Communications, 2014, 5, pp.5005. ⟨10.1038/ncomms6005⟩. ⟨hal-01712223⟩