Open AccessLoss of WNT‐TCF addiction and enhancement of HH‐GLI1 signalling define the metastatic transition of human colon carcinomas
Author(s) -
Varnat Frédéric,
SieglCachedenier Irene,
Malerba Monica,
Gervaz Pascal,
Ruiz i Altaba Ariel
Publication year - 2010
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201000098
Subject(s) - wnt signaling pathway , gli1 , cancer research , hedgehog , epithelial–mesenchymal transition , stem cell , downregulation and upregulation , sonic hedgehog , biology , metastasis , cancer , medicine , microbiology and biotechnology , signal transduction , genetics , gene
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.