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

Published in EMBO molecular medicine. 2010, vol. 2, no. 11, p. 440-457
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/analysisCarcinoma/pathology/*physiopathologyColonic Neoplasms/pathology/*physiopathologyGene Expression ProfilingGlycoproteins/analysisHedgehog Proteins/*metabolismHumansNeoplasm Metastasis/pathology/*physiopathologyPeptides/analysisStem CellsTCF Transcription Factors/*metabolismTranscription Factors/*metabolismWnt Proteins/*metabolism
PMID: 20941789
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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 https://archive-ouverte.unige.ch/unige:21368

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Deposited on : 2012-05-23

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