en
Scientific article
English

Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas

Published inEMBO molecular medicine, vol. 2, no. 11, p. 440-457
Publication date2010
Abstract

Previous studies demonstrate the initiation of colon cancers through deregulation of WNT-TCF signalling. An accepted but untested extension of this finding is that incurable metastatic colon carcinomas (CCs) universally remain WNT-TCF-dependent, prompting the search for WNT-TCF inhibitors. CCs and their stem cells also require Hedgehog (HH)-GLI1 activity, but how these pathways interact is unclear. Here we define coincident high-to-low WNT-TCF and low-to-high HH-GLI transitions in patient CCs, most strikingly in their CD133(+) stem cells, that mark the development of metastases. We find that enhanced HH-GLI mimics this transition, driving also an embryonic stem (ES)-like stemness signature and that GLI1 can be regulated by multiple CC oncogenes. The data support a model in which the metastatic transition involves the acquisition or enhancement of a more primitive ES-like phenotype, and the downregulation of the early WNT-TCF programme, driven by oncogene-regulated high GLI1 activity. Consistently, TCF blockade does not generally inhibit tumour growth; instead, it, like enhanced HH-GLI, promotes metastatic growth in vivo. Treatments for metastatic disease should therefore block HH-GLI1 but not WNT-TCF activities.

Keywords
  • Antigens, CD/analysis
  • Carcinoma/pathology/*physiopathology
  • Colonic Neoplasms/pathology/*physiopathology
  • Gene Expression Profiling
  • Glycoproteins/analysis
  • Hedgehog Proteins/*metabolism
  • Humans
  • Neoplasm Metastasis/pathology/*physiopathology
  • Peptides/analysis
  • Stem Cells
  • TCF Transcription Factors/*metabolism
  • Transcription Factors/*metabolism
  • Wnt Proteins/*metabolism
Citation (ISO format)
VARNAT, Frédéric et al. Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas. In: EMBO molecular medicine, 2010, vol. 2, n° 11, p. 440–457. doi: 10.1002/emmm.201000098
Main files (1)
Article
accessLevelRestricted
Identifiers
ISSN of the journal1757-4676
546views
0downloads

Technical informations

Creation05/23/2012 8:58:32 AM
First validation05/23/2012 8:58:32 AM
Update time03/14/2023 5:36:20 PM
Status update03/14/2023 5:36:20 PM
Last indexation02/12/2024 8:20:55 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack