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

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.