Title:Recent Insights into Notch Signaling in Embryonal Rhabdomyosarcoma
Volume: 17
Issue: 11
Author(s): Beatrice Conti, Katherine K. Slemmons, Rossella Rota and Corinne M. Linardic
Affiliation:
Keywords:
Notch, embryonal rhabdomyosarcoma, skeletal muscle, myogenesis, muscular dystrophy, targeted therapy, pediatric
cancers.
Abstract: The Notch signaling pathway is an evolutionarily conserved developmental
network critical for embryonic and postnatal regulation of tissue growth, homeostasis,
and repair. Signaling is initiated when transmembrane Notch ligands bind to transmembrane
Notch receptors on nearby cells. Sequential proteolytic steps generate an activated Notch fragment that translocates
to the nucleus, where it drives activation of canonical Notch target genes. In skeletal muscle, Notch signaling governs
myogenic cell fate and stem cell maintenance. In the human soft tissue sarcoma rhabdomyosarcoma, which bears
markers of skeletal muscle commitment and so is thought to be related to the skeletal muscle lineage, Notch signaling is
also found to be upregulated and dysregulated. This review provides an overview of Notch signaling during normal embryonic
and postnatal myogenesis, information on the recently discovered aberrant Notch signaling occurring in muscular
dystrophies, the upregulation and mechanism of Notch signaling in the embryonal variant of rhabdomyosarcoma and related
soft tissue sarcomas, and Notch cross-talk with other metazoan developmental pathways including Hippo, Hedgehog,
Wnt, and TGF-β. The review concludes with updates on current promising efforts to target and inhibit Notch signaling
in human sarcomas including rhabdomyosarcoma.
