gms | German Medical Science

57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

12. - 15.09.2012, Erlangen

Banner: 57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie

Active Wnt/ß-Catenin signaling impairs tumor growth in Sonic-hedgehog dependent medulloblastoma

Meeting Abstract

  • presenting/speaker Julia Pöschl - Zentrum für Neuropathologie, München, Germany
  • Martin Bartels - Zentrum für Neuropathologie, München, Germany
  • Edoardo Bianchi - Zentrum für Neuropathologie, München, Germany
  • Daniel Grammel - Zentrum für Neuropathologie, München, Germany
  • Hans Kretzschmar - Zentrum für Neuropathologie, München, Germany
  • Ulrich Schüller - Zentrum für Neuropathologie, München, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnOP13

DOI: 10.3205/12dgnn013, URN: urn:nbn:de:0183-12dgnn0136

Veröffentlicht: 11. September 2012

© 2012 Pöschl et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

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::SmoM2Fl/+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.