Aberrant myogenic activation in endothelial cells can drive fusion-negative rhabdomyosarcoma (FN-RMS).

  • Major finding: Aberrant myogenic activation in endothelial cells can drive fusion-negative rhabdomyosarcoma (FN-RMS).

  • Approach: Genetic fate mapping in a mouse model of mutant SMO–driven FN-RMS uncovers the cell of origin.

  • Impact: An endothelial cell of origin may explain the development of FN-RMS at sites devoid of skeletal muscle.

Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma with histologic features of embryonic skeletal muscle that is divided into two histologic subtypes—alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). The majority of ARMS tumors harbor PAX3–FOXO1 or PAX7–FOXO1 fusion proteins, which are associated with poor outcomes, and ARMS is thought to arise from muscle progenitor cells in developing skeletal muscle. However, fusion-negative (FN) ARMS, lacking PAX3/PAX7–FOXO1, can arise in sites without skeletal muscle, suggesting the possibility that some FN-ARMS may derive from non-myogenic cells. To determine the cell of origin of FN-RMS, Drummond, Hanna, and colleagues used a previously developed mouse model of head and neck FN-RMS driven by constitutive activation of a mutant Smo allele (SmoM2) driven by aP2-Cre. Crossing the SmoM2/+ mice with aP2-Cre;mT/mG mice harboring the Rosa26mT/mG reporter allele allowed for genetic fate mapping of progenitor cells. aP2-Cre labeled cells in both adipose tissue and skeletal muscle, but these tissues were unaffected by SMOM2 expression. Instead, SMOM2 expression in Cre-expressing endothelial progenitor cells in the skeletal muscle interstitium promoted myogenic transdifferentiation and RMS tumorigenesis, suggesting an endothelial cell of origin for these FN-RMS tumors. The resulting tumors expressed myogenic genes required for head and neck muscle development including Tbx1, Pitx2, Tcf21, and Msc, and also retained expression of endothelial genes including Kdr (also known as Vegfr2), Gata2, Sox18, and Cdh5. Activation of the hedgehog pathway induced aberrant expression of myogenic genes in Kdr-expressing endothelial progenitor cells, which may drive RMS tumorigenesis. Taken together, these findings suggest that FN-RMS can arise from endothelial progenitor cells with aberrant myogenic factor expression induced by mutant SMO, and may explain the genesis of FN-RMS in sites without skeletal muscle.

Drummond CJ, Hanna JA, Garcia MR, Devine DJ, Heyrana AJ, Finkelstein D, et al. Hedgehog pathway drives fusion-negative rhabdomyosarcoma initiated from non-myogenic endothelial progenitors. Cancer Cell 2018;33:108–24.e5.

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