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

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Schneider,  André
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Braun,  Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Nitzki, F., Cuvelier, N., Draeger, J., Schneider, A., Braun, T., & Hahn, H. (2016). Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells. ONCOGENE, 35(22), 2923-2931. doi:10.1038/onc.2015.346.


Cite as: https://hdl.handle.net/21.11116/0000-0001-C12C-4
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.