A Novel Notch-YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma

• Published in: Molecular cancer research Vol. 15; no. 12; pp. 1777 - 1791
• Main Authors: Slemmons, Katherine K, Crose, Lisa E S, Riedel, Stefan, Sushnitha, Manuela, Belyea, Brian, Linardic, Corinne M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.12.2017
• Subjects: Cancer; Children; Circuits; Gene expression; Genes; In vivo methods and tests; Inhibition; Muscles; Notch protein; Pharmacology; Rhabdomyosarcoma; Risk groups; Sarcoma; Signal transduction; Signaling; Skeletal muscle; Stem cells; Therapeutic applications; Tumorigenesis; Tumors; Yes-associated protein
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-17-0004

Rhabdomyosarcoma (RMS), a cancer characterized by skeletal muscle features, is the most common soft-tissue sarcoma of childhood. While low- and intermediate-risk groups have seen improved outcomes, high-risk patients still face a 5-year survival rate of <30%, a statistic that has not changed in over 40 years. Understanding the biologic underpinnings of RMS is critical. The developmental pathways of Notch and YAP have been identified as potent but independent oncogenic signals that support the embryonal variant of RMS (eRMS). Here, the cross-talk between these pathways and the impact on eRMS tumorigenesis is reported. Using human eRMS cells grown as three-dimensional (3D) rhabdospheres, which enriches in stem cells, it was found that Notch signaling transcriptionally upregulates gene expression and YAP activity. Reciprocally, YAP transcriptionally upregulates the Notch ligand genes and and the core Notch transcription factor This bidirectional circuit boosts expression of key stem cell genes, including , which is functionally required for eRMS spheres. Silencing this circuit for therapeutic purposes may be challenging, because the inhibition of one node (e.g., pharmacologic Notch blockade) can be rescued by upregulation of another (constitutive YAP expression). Instead, dual inhibition of Notch and YAP is necessary. Finally, supporting the existence of this circuit beyond a model system, nuclear Notch and YAP protein expression are correlated in human eRMS tumors, and YAP suppression decreases Notch signaling and SOX2 expression. This study identifies a novel oncogenic signaling circuit driving eRMS stemness and tumorigenesis, and provides evidence and rationale for combination therapies co-targeting Notch and YAP. .