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Notch signaling is not essential in sonic hedgehog-activated medulloblastoma

Oncogene volume 29, pages 3865–3872 (2010)Cite this article

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Abstract

Dysregulated signal transduction through the notch pathway has been noted in human and mouse medulloblastoma studies. Gamma secretase inhibitors (GSIs) impair notch signaling by preventing the cleavage of transmembrane notch proteins into their active intracellular domain fragments. Previous studies have shown that GSI treatment caused apoptosis and impaired medulloblastoma cell engraftment in xenograft systems. In this study, we used in vivo genetic and pharmacologic approaches to quantify the contribution of notch signaling to sonic hedgehog (shh)-activated mouse medulloblastoma models. In contrast to prior in vitro studies, pharmacologic inhibition of notch pathways did not reduce the efficiency of medulloblastoma xenotransplantation nor did systemic therapy impact tumor size, proliferation, or apoptosis in genetically engineered mouse medulloblastoma models. The incidence and pathology of medulloblastomas driven by the SmoA1 transgene was unchanged by the bi-allelic absence of Notch1, Notch2, or Hes5 genes. These data show that notch signaling is not essential for the initiation, engraftment, or maintenance of sonic hedgehog pathway-driven medulloblastomas.

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Acknowledgements

We are grateful to Dr Francois Guillemot for providing the Hes5-null mice, to Freddy Radtke for the notch1 conditional knockout mice, to Thomas Gridley for the notch2 conditional knockout mice, and to Dr Irwin Bernstein for providing the 18G anti-Notch antibody and advice. The gamma secretase inhibitor MRK-003 was provided by Merck Research Laboratories, which also provided partial funding for the studies. This work was supported by NIH Grants 5R01CA112350-04, 5R01CA114567-04, 5T32CA009351, and 5K12CA076930.

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  1. B A Hatton and E H Villavicencio: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    B A Hatton, E H Villavicencio, J Pritchard, M LeBlanc, S Hansen, M Ulrich, S Ditzler, B Pullar, M R Stroud & J M Olson

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  1. B A Hatton
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  2. E H Villavicencio
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  3. J Pritchard
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  4. M LeBlanc
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  5. S Hansen
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  7. S Ditzler
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  8. B Pullar
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  9. M R Stroud
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  10. J M Olson
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Correspondence to J M Olson.

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Competing interests

Merck Research Laboratories provided the GSI MRK-003 and partial funding for the studies, but did not have a role in designing the studies or collecting or analyzing the resulting data. Merck Research Laboratories reviewed the manuscript before its submission to Oncogene and stated no conflict in including all data and results for publication.

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Hatton, B., Villavicencio, E., Pritchard, J. et al. Notch signaling is not essential in sonic hedgehog-activated medulloblastoma. Oncogene 29, 3865–3872 (2010). https://doi.org/10.1038/onc.2010.142

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