A Mouse Model of Rhabdomyosarcoma Originating from the Adipocyte Lineage

SummaryRhabdomyosarcoma (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.

► Hedgehog pathway activation in the adipose lineage induces embryonal rhabdomyosarcoma
► Adipose-lineage-derived ERMS display genetic signature of activated satellite cells
► Gene expression patterns of human and aP2-Cre;SmoM2 mouse ERMS are similar