Abstract IA06: Dysregulated Hippo signaling in childhood rhabdomyosarcoma
Linardic, CM
Published in: Molecular Cancer Research
Rhabdomyosarcoma (RMS) is a mesenchymal cancer of skeletal muscle histogenesis and the most common soft tissue sarcoma of childhood. Survival for children with high-risk disease is less than 30% and has not improved in over four decades, underscoring the need for a deeper understanding of the dysregulated pathways at the molecular level. Recently, we and others have identified Hippo signaling as one of the developmental pathways hijacked by RMS, leading to uncontrolled RMS cell and tumor growth. Here we will describe the nature of dysregulated Hippo signaling in the two most common forms of RMS, known as fusion-negative RMS and fusion-positive RMS (formerly ERMS and ARMS, respectively). Fusion status refers to the absence or presence of RMS-specific PAX-FOXO1 fusion oncogenes, mutant transcription factors that portend a poor clinical outcome. In fusion-negative RMS, we find a critical role for YAP1 in tumor initiation and tumor maintenance, with YAP1 engaged in a feed-forward loop with the Notch pathway to support RMS cancer cell stemness. In fusion-positive RMS, we also find dysregulated canonical Hippo signaling supporting tumorigenic phenotypes. However, there is an additional unanticipated role for PAX3-FOXO1 in restraining noncanonical Hippo signaling. Complementary tumor models used to interrogate Hippo signaling in RMS, including patient-derived cell lines, primary human myoblast-based models, and genetically engineered mouse models, will be presented. Finally, the discrete knowledge gaps to be filled and the therapeutic opportunities that will arise from preclinical harnessing of the Hippo pathway in this and other childhood soft tissue sarcomas will be considered.Citation Format: Corinne M. Linardic. Dysregulated Hippo signaling in childhood rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA06.
