Transdifferentiation of endothelial progenitor cells into rhabdomyosarcoma defined by hedgehog signaling competence

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma resembling developing skeletal muscle, but tumors are found in sites devoid of skeletal muscle, suggesting a non-myogenic cell of origin. We previously described an endothelial progenitor cell-derived model of RMS by activating a conditional, constitutively active Smoothened mutant (SmoM2) with aP2-Cre. We sought to further identify the endothelial progenitor cell of origin in our aP2-Cre;R26^SmoM2 model using mice with more endothelial-specific Cre recombinase expression. Using lineage tracing of embryonic endothelial progenitor cells and mature, adult endothelial cells, we show that a selected subset of endothelial progenitor cells can transform into RMS. These endothelial progenitor cells have a specific window during embryogenesis with a capacity for transformation into RMS that is dictated by the presence of primary cilia and Sonic Hedgehog signaling pathway competency. These findings deepen our understanding of endothelial differentiation and the connections between normal development and oncogenesis in children.