title: Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells.
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.
authors.affiliation: Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Nitzki
authors.affiliation: Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Cuvelier
authors.affiliation: Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dräger
authors.affiliation: Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Braun
authors.affiliation: Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hahn
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D009154:Mutation; D000072079:Patched Receptors / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway
chemical_list: D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D051880:Receptors, Notch; C064045:delta protein