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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Lineage
  • DNA Primers / genetics
  • Disease Models, Animal*
  • Epithelial-Mesenchymal Transition / physiology*
  • Exome / genetics
  • Gastrointestinal Tract / metabolism
  • Gastrointestinal Tract / physiology*
  • Genotype
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Neoplasm Metastasis / physiopathology*
  • Receptor, Notch1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA Primers
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Tumor Suppressor Protein p53
  • Green Fluorescent Proteins