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.

Differential expression profiles of the Hedgehog signaling pathway between microsatellite-stable and microsatellite-unstable colorectal cancers

“…SHH activation was associated with downstream activation of Gli1 and FOXM1 transcription factors known to promote cell proliferation through the induction of the cyclin genes (20,21). Gli1 level and activity may thus be modulated by multiple oncogenes and the environment of the cancer cells (22). We may hypothesize that some of these genes are involved in the Hh signal pathway.…”

Crosstalk between Wnt/β-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy

“…28 Oncogenic KRAS mutant could promote Gli1 by downstream RAF/ MEK/ERK and PI3K/AKT signaling cascades. 29,30 In addition, inactive p53 and lost PTEN expression have been proven to result in upregulated Gli1 activity in colon cancer cells. 30 The mechanisms of aberrant Hedgehog/Gli signaling associated with cancer are diverse.…”

“…29,30 In addition, inactive p53 and lost PTEN expression have been proven to result in upregulated Gli1 activity in colon cancer cells. 30 The mechanisms of aberrant Hedgehog/Gli signaling associated with cancer are diverse. 31 In colon cancer, the precise mechanism is still unclear.…”

“…30,[37][38][39][40][41][42] To summarize, possible molecular crosstalk between 2 pathways include the following (Fig. 3):…”

“…42,46,47 In addition, inactive mutation of p53 or loss of PTEN in colon cancer could stimulate both pathways by activating b-catenin and Gli1. 10,30 Studies have shown that high levels of functional p53 could lead to a reduction of the amount and transcriptional activity of b-catenin. 8,9 PTEN knockdown can increase the stabilization of b-catenin through activating PI3K/AKT pathway.…”