gms | German Medical Science

Medulloblastoma is the most common malignant brain tumor in childhood and about 30% of cases are characterized by activated Sonic-hedgehog (Shh) signaling. Shh is known to be crucial for the proliferation of cerebellar granule neuron precursors (cGNPs) and constitutive activation of the Shh pathway in these cells leads to the formation of medulloblastoma. In contrast, constitutive activation of Wnt/β-catenin signaling in cGNPs results in severe proliferation deficits and premature differentiation.

In order to develop new therapeutic strategies to treat patients with medulloblastoma, we investigated whether the activation of Wnt/β-catenin signaling would similarly impair the growth of medulloblastomas that have arisen from cGNPs due to constitutive Shh signaling. We simultaneously activated Shh and Wnt/β-catenin signaling in primary cultures of cGNPs and found that constitutive activation of Wnt/β-catenin signaling significantly reduced Shh-dependent proliferation in vitro.In order to confirm these results in vivo, we used Math1-cre::SmoM2^Fl/+mice, which represent a well-established model for cGNP-derived Shh-associated medulloblastoma. Introducing a Ctnnb1(ex3)^Fl/+allele into this model resulted in a simultaneous activation of Wnt signaling in tumor cells, a significantly reduced tumor cell proliferation and prolonged survival of the mice. Interestingly, this inhibitory effect of Wnt on Shh signaling appeared to be specific for transformed cGNPs. Analogous experiments using anhGFAP-cre driver line showed similar results within the cerebellum, but a massive expansion of precursor pools in the forebrain.

These results shed new light on critical interactions between Shh and Wnt signaling in the central nervous system and provide a basis for future options to treat Shh dependent medulloblastoma using Wnt/β-catenin signaling agonists.