Journal
EMBO MOLECULAR MEDICINE
Volume 2, Issue 11, Pages 440-457Publisher
WILEY
DOI: 10.1002/emmm.201000098
Keywords
colon cancer; Hedgehog-Gil; metastasis; stem cell; Wnt-Tcf
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Funding
- Human Frontiers Science Project Long Term Fellowship
- Departement d'Instruction Publique of Geneva
- Swiss National Science Foundation
- Jeantet and Swissbridge Foundation
- Swiss Cancer League
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Previous studies demonstrate the initiation of colon cancers through deregulation of INNT-TCF signalling. An accepted but untested extension of this finding is that incurable metastatic colon carcinomas (CCs) universally remain VVNT-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 sternness signature and that all 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 GM 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.
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