Cell specific crosstalk of the Wnt/β-catenin and the Shh pathway: implications for tumor development and regression
- 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
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.