title: Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut.
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.
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Maia
authors.initials: M
authors.lastname: Chanrion
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
authors.forename: Inna
authors.initials: I
authors.lastname: Kuperstein
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Barrière
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: El Marjou
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Danijela
authors.initials: D
authors.lastname: Vignjevic
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Lev
authors.initials: L
authors.lastname: Stimmer
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Cell and Tissue Imaging Facility, PICT-IBiSA, CNRS, UMR 144, Paris 75248, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Paul-Gilloteaux
authors.affiliation: 1] Inserm U735, Hôpital René Huguenin, 92210 Saint-Cloud, France [2] Institut Curie, Hôpital René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Silvina Dos Reis
authors.initials: Sdos R
authors.lastname: Tavares
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Giuseppe-Fulvio
authors.initials: GF
authors.lastname: Boccia
authors.affiliation: Institut Curie, Centre Hospitalier, Paris 75248, France.
authors.forename: Wulfran
authors.initials: W
authors.lastname: Cacheux
authors.affiliation: Institut Curie, Centre Hospitalier, Paris 75248, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR3215, Paris 75248, France [3] Inserm U934, Paris 75248, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fre
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
authors.forename: Loredana
authors.initials: L
authors.lastname: Martignetti
authors.affiliation: Next-Generation Sequencing Platform, Institut Curie, Paris 75248, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Legoix-Né
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Girard
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR168, Paris 75248, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Fetler
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Louvard
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] Inserm, U900, Paris 75248, France.
authors.forename: Andreï
authors.initials: A
authors.lastname: Zinovyev
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris 75248, France [2] CNRS UMR 144, Paris 75248, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
mesh_terms: D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D059472:Exome / Q000235:genetics; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000502:physiology*; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins