A mouse model of rhabdomyosarcoma originating from the adipocyte lineage.
Rhabdomyosarcoma (RMS) is an aggressive skeletal muscle-lineage tumor composed of malignant myoblasts that fail to exit the cell cycle and are blocked from fusing into syncytial muscle. Rhabdomyosarcoma includes two histolopathologic subtypes: alveolar rhabdomyosarcoma, driven by the fusion protein PAX3-FOXO1 or PAX7-FOXO1, and embryonal rhabdomyosarcoma (ERMS), which is genetically heterogeneous. Here, we show that adipocyte-restricted activation of Sonic hedgehog signaling through expression of a constitutively active Smoothened allele in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human ERMS with high penetrance. Our findings suggest that adipocyte progenitors can be a cell of origin for Sonic hedgehog-driven ERMS, showing that RMS can originate from nonskeletal muscle precursors.
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Mark E
ME
Hatley
Wei
W
Tang
Matthew R
MR
Garcia
David
D
Finkelstein
Douglas P
DP
Millay
Ning
N
Liu
Jonathan
J
Graff
Rene L
RL
Galindo
Eric N
EN
Olson
D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D019070:Cell Lineage; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D051379:Mice; D051763:PAX7 Transcription Factor / Q000502:physiology; D018233:Rhabdomyosarcoma, Embryonal / Q000209:etiology* / Q000473:pathology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D053823:Hedgehog Proteins; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse