A Case of mistaken identity: Rhabdomyosarcoma development from endothelial progenitor cells

Abstract

Rhabdomyosarcoma (RMS) histologically resembles developing skeletal muscle and is thought to solely originate from a differentiation block in muscle progenitors. We demonstrate that RMS can arise from endothelial progenitor cells following reprogramming and myogenic transdifferentiation. These results highlight how tumors with identical morphological features can arise from different cell types and offer insight into RMS formation in non-myogenic tissue.

Keywords: cell of origin; endothelial; hedgehog; muscle; pediatric cancer; reprogramming; rhabdomyosarcoma; sarcoma; skeletal muscle; transdifferentiation.

Figure 1.

Role for endothelial progenitor reprogramming by Hedgehog in rhabdomyosarcoma oncogenesis. A) Model of endothelial cell and skeletal muscle development from Kinase insert domain receptor positive (KDR⁺) progenitors in the pharyngeal mesoderm on a Waddington epigenetic landscape. B) Proposed model of fusion-negative rhabdomyosarcoma tumorigenesis. Constitutive activation of Hedgehog signaling (Shh) by expression of constitutively active oncogenic SMOOTHENED (SmoM2) in aP2-Cre expressing endothelial progenitor cells results in their embryonic expansion, reprogramming and myogenic transdifferentiation into fusion-negative rhabdomyosarcoma. Immunostaining for Tomato (Red), Myosin Heavy Chain (Green) and DAPI (Blue). Abbreviations in figure as follows: adipose protein 2 (aP2), T-box 1 (TBX1), Paired-like homeodomain transcription factor 2 (PITX2), Transcription factor 21 (TCF21), rhabdomyosarcoma (RMS). Adapted from.