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Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells

Oncogene volume 35, pages 2923–2931 (2016)Cite this article

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Abstract

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In children, the 2 major RMS subtypes are alveolar and embryonal RMS. Aberrant Hedgehog/Patched1 (Hh/Ptch) signaling is a hallmark of embryonal RMS. We demonstrate that mice carrying a Ptch mutation in mesodermal Delta1-expressing cells develop embryonal-like RMS at a similar rate as mice harboring a Ptch mutation in the germline or the brachury-expressing mesoderm. The tumor incidence decreases dramatically when Ptch is mutated in Myf5- or Pax3-expressing cells. No RMS develop from Myogenin/Mef2c-expressing cells. This suggests that Hh/Ptch-associated RMS are derived from Delta1-positive, Myf5-negative, Myogenin-negative and Pax3-negative mesodermal progenitors that can undergo myogenic differentiation but lack stable lineage commitment. Additional preliminary genetic data and data on mesodermal progenitors further imply an interplay of Hh/Ptch and Delta/Notch signaling activity during RMS initiation. In contrast, Wnt signals supposedly suppress RMS formation because RMS multiplicity decreases after inactivation of the Wnt-inhibitor Wif1. Finally, our results strongly suggest that the tumor-initiating event determines the lineage of RMS origin.

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Acknowledgements

We thank Lars Wittler and Ludger Hartmann for Wntvt/vt mice, Walter Birchmeier and Felix Brembeck for β-catflox/flox mice and Christoph Englert and David Thomas for Wif1−/− mice. We are grateful to Susan Peter and Stefan Wolf for excellent animal care. We thank Anke Frommhold, Ina Heβ and Tobias Goldak for technical assistance and Walter Schulz-Schaeffer (Institute of Neuropathology, University Medical Center Göttingen) and Ilona Skerjanc for useful advice. This work was supported by the DFG Grant HA2197/7-1 to HH.

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Authors and Affiliations

  1. Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany

    F Nitzki, N Cuvelier, J Dräger & H Hahn

  2. Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

    A Schneider & T Braun

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  1. F Nitzki
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Correspondence to H Hahn.

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Nitzki, F., Cuvelier, N., Dräger, J. et al. Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells. Oncogene 35, 2923–2931 (2016). https://doi.org/10.1038/onc.2015.346

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