Abstract LB_A23: The role of SMARCA1 in Rhabdomyosarcoma and skeletal muscle differentiation

Abstract

Abstract Background: Rhabdomyosarcoma (RMS) is the most common soft tissue of pediatric sarcoma, and studies demonstrate that RMS arises from skeletal muscle precursor cells. RMS, genetically and histologically, is divided into two subtypes: PAX-FOXO1 fusion positive (alveolar) RMS (aRMS), which is driven by chromosomal translocation involving PAX3 or PAX7 genes with FOXO1 and PAX-FOXO1 fusion negative (embryonal) RMS (eRMS), which is marked by mutations in RAS isoforms and some genes such as TP53, PIK3CA, CTNNB1 and FGFR4. Chromatin was one of the earliest identified targets for cancer therapy. Several chromatin remodeling proteins are associated with cancer progression processes such as proliferation, differentiation, apoptosis, and tumorigenesis. Components of chromatin remodeling complexes, such as the imitation switch (ISWI) complex, have been classified as both oncogenes and tumor suppressors. The ISWI family protein, SMARCA1 (also known as SNF2L), has been implicated in tumorigenesis for several cancer types. ISWI complexes regulate cell differentiation and proliferation in other cell systems, but their impact in myogenesis is not well understood. In this study, we will characterize the function of SMARCA1 in RMS cells and skeletal muscle. We hypothesize that SMARCA1 acts to modulate chromatin accessibility, and drive RMS tumorigenic growth. Methods: We will use RNA-seq, ATAC-seq, and CUT&RUN to study the impact of SMARCA1 deletion in RMS cells. Furthermore, phenotypic experiments will be performed to determine the influence of SMARCA1 on differentiation. Results: SMARCA1 is expressed at a high level in RMS tissues but not in muscle tissues. Furthermore, our findings show that SMARCA1 is modestly upregulated during the differentiation in normal myogenesis. Curiously, eRMS cell lines show no change in the protein level of SMARCA1 when treated with a MEK inhibitor, trametinib. Analysis of gene clusters in RMS transcriptomic data of indicated that SMARCA1 co-expresses with a RAS effector, RALA. SMARCA1 also clustered with HDAC2. In addition, SMARCA1 interacted with HDAC2 in RMS cells as determined by co-immunoprecipitation experiments. Conclusions: This study will deepen our understanding of how SMARCA1 impacts RMS differentiation and proliferation and may credential SMARCA1 as a novel therapeutic target in rhabdomyosarcoma. Citation Format: Ashwaq K Aljabri, Katie E Hebron, Yuliya Kriga, Juan Manuel Caravaca, Aiysha Althobaiti, Alex Emmons, Stacey Stauffer, Angela Kim, Lauren Stoak, Morgan Porter, Jyoti Shetty, Peter Fitzgerald, Bao Tran, Matthew Geisler, Judith K Davie, Marielle E Yohe. The role of SMARCA1 in Rhabdomyosarcoma and skeletal muscle differentiation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A23.