YAP1 Is an Oncogenic Driver in Embryonic Rhabdomyosarcoma

Embryonal rhabdomyosarcoma (ERMS), the most common subtype of soft-tissue sarcoma in children, is characterized by myoblast proliferation and inhibition of myogenic differentiation; however, the oncogenic drivers that regulate ERMS development are poorly understood. Nuclear localization and activation of the transcriptional cofactor YAP1 promotes proliferation and tumor formation in epithelial tissues, but its potential function in RMS is poorly understood. Tremblay and colleagues found that human ERMS samples exhibited increased expression and nuclear localization of YAP1 compared with PAX3/7–FOXO1A fusion-positive alveolar rhabdomyosarcoma (ARMS) samples. Muscle-specific expression of YAP1 in three transgenic mouse models revealed that YAP1 hyperactivity in activated but not quiescent satellite progenitor cells induced the formation of ERMS-like tumors with high penetrance and short latency. In contrast, reduction in YAP1 expression resulted in regression of ERMS tumors and expression of markers of mature skeletal muscle differentiation, suggesting that sustained YAP1 hyperactivity causes ERMS by promoting proliferation and imposing a differentiation block. Consistent with this idea, together with its cofactor TEA domain family member 1 (TEAD1), YAP1 directly stimulated the expression of proliferative genes and RMS-associated oncogenes and suppressed terminal myogenic differentiation genes by upregulating inhibitors of prodifferentiation myogenic transcription factors. In addition, YAP1–TEAD1 occupancy adjacent to myogenic transcription factors on myogenic differentiation–associated loci impaired recruitment of myogenic differentiation 1 (MYOD1) and myocyte enhancer factor 2 (MEF2) to these loci in mouse ERMS cells. Analysis of primary human RMS samples revealed that high YAP1 activity in ERMS and fusion-negative ARMS was strongly associated with increased tumor stage and poor prognosis. Furthermore, knockdown of YAP1 decreased tumorigenicity and enhanced myogenic differentiation in human ERMS cells. These studies identify YAP1 as an oncogene in ERMS and suggest that its inhibition may become an effective differentiation therapy approach in these tumors.

Tremblay AM, Missiaglia E, Galli GG, Hettmer S, Urcia R, Carrara M, et al. The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation. Cancer Cell 2014;26:273–87.