Dr Pascal Gervaz

Chirurgien FMH, chirurgie interne & chirurgie viscérale



Loss of WNT-TCF Addiction and Enhancement of HH-GLI1 Signalling Define the Metastatic Transition of Human Colon Carcinomas




by Varnat F, Siegl-Cachedenier I, Malerba M, Gervaz P, Ruiz i Altaba A.




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.


The full text of this arcticle can be found here.



in EMBO Molecular Medicine 2010 Nov; 2(11):440-57. doi: 10.1002/emmm. 201000098.