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Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells
F Nitzki1, N Cuvelier1, J Dräger1
1Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
Insights
Aberrant Hedgehog/Patched1 signaling drives embryonal rhabdomyosarcoma (RMS) in mice. The study identifies specific mesodermal progenitor cells as the origin of these pediatric tumors.
Area of Science:
- Developmental biology
- Oncology
- Genetics
Background:
- Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma.
- Embryonal RMS (ERMS) is characterized by aberrant Hedgehog/Patched1 (Hh/Ptch) signaling.
- Understanding the cellular origin of RMS is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the cellular origins of Hh/Ptch-associated rhabdomyosarcoma.
- To determine the role of specific mesodermal progenitor populations in RMS development.
- To explore the interplay between signaling pathways in RMS initiation.
Main Methods:
- Utilized a mouse model with mutations in the Ptch gene within specific mesodermal cell populations.
- Analyzed tumor incidence and characteristics based on the genetic background of the mutations.
- Investigated the expression patterns of key developmental genes (Myf5, Pax3, Myogenin, Mef2c, Delta1) in progenitor cells.
Main Results:
- Ptch mutations in Delta1-expressing mesodermal cells led to embryonal-like RMS.
- Tumor incidence was significantly reduced when Ptch was mutated in Myf5- or Pax3-expressing cells.
- Hedgehog/Patched1 and Delta/Notch signaling pathways appear to interplay during RMS initiation.
- Wnt signaling may suppress RMS formation, as Wif1 inactivation decreased tumor multiplicity.
Conclusions:
- Hh/Ptch-associated RMS originates from Delta1-positive, Myf5/Pax3/Myogenin-negative mesodermal progenitors.
- These progenitors possess myogenic potential but lack stable lineage commitment.
- The initial tumor-initiating event dictates the lineage of RMS origin.
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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