- Cell specific crosstalk of the Wnt/β-catenin and the Shh pathway: implications for tumor development and regression (2011)
- The canonical Wnt/β-catenin and the Shh pathway as well as the Notch signaling cascade are key regulators in stem cell biology and are independently associated with the development of cancer. Despite the knowledge of a balanced signaling for cellular maintenance, the fundamental biochemical mechanisms of crosstalk are still poorly understood. This study demonstrates that the outcome of interaction between Wnt and Shh is cell type specific. A combined inhibitory mechanism of the Shh and Notch2/Jagged2 pathways on dominant active β-catenin signaling in the adult tongue epithelium keeps Wnt/β-catenin signaling restricted to physiological tolerable levels. In the opposite crosstalk the activation of Wnt/β-catenin signaling in medulloblastoma (MB) of the Shh subtype, in turn inhibits the Hh pathway. The inhibitory mechanism of Shh and Notch2/Jagged2 on Wnt/β-catenin signaling is independent of the degradation complex of β-catenin and takes place inside the nucleus. Furthermore, the negative feedback on Wnt/β-catenin signaling by the Shh pathway relies on transcriptional activity of Gli1/2A. Inhibition of Gli1/2A with the specific inhibitor GANT61 abrogated the negative impact of Shh on β-catenin signaling in vitro. Although the negative feedback loop of Shh is still functional in human SCC25 cells, the inhibitory effect of Notch2/Jagged2 is lost and contributes to the cancerogenic phenotype of these cells. In the inverse situation, the activation of β−catenin signaling has a negative feedback on constantly active Shh signaling and significantly inhibits the Hh pathway. This was shown in Ptch+/- and Math1-Cre:SmoM2Fl/+ MB tumor spheres in vitro, in which inhibition of sphere formation and growth was observed and Hh target gene transcription was down-regulated. This demonstrates for the first time that the activation of canonical Wnt/β-catenin signaling in primary MB cells with a Hh pathway over-activation has a negative effect on the growth of these cells in vitro. In summary the results show that crosstalk of Wnt/β-catenin and Shh signaling has context specific outcome on pathway activity. Elucidation of the molecular interactions will improve our understanding of Wnt and Hh associated tumors and contribute to the development of new therapeutic strategies.