Abstract B042: A differentiation-driven migration program in rhabdomyosarcoma (RMS) is governed by a BRD1-MYOG transcriptional axis

Abstract

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma marked by cellular heterogeneity along the myogenic differentiation spectrum, yet the relationship between differentiation state and metastatic potential remains poorly defined. In epithelial cancers, metastasis is typically driven by dedifferentiation via epithelial–mesenchymal transition (EMT). In contrast, we hypothesized that RMS co-opts a differentiation-associated program to promote migration. Myogenin (MYOG), a master regulator of mid-to-late myogenic differentiation, marks a committed myocyte-like state. In a zebrafish RMS model, MYOG-positive cells have been shown to exhibit enhanced migratory velocity, intravasation, and seeding capacity compared to less differentiated tumor cell populations. To identify upstream regulators of this phenotype, we performed a targeted knockdown screen of epigenetic factors and identified BRD1, a bromodomain-containing transcriptional regulator, as a previously unrecognized driver of RMS cell migration. BRD1 knockdown by shRNA significantly impaired migration and reduced MYOG expression, while MYOG knockdown phenocopied the migratory defect, establishing a functional BRD1–MYOG axis. Immunofluorescence analyses demonstrated that actively migrating cells are enriched for both BRD1 and MYOG expression. These findings were independently validated using multiple shRNA constructs across fusion-positive (PAX3/7::FOXO1-driven) and fusion-negative (RAS/receptor tyrosine kinase-driven) RMS models, indicating conserved relevance across molecular subtypes. Notably, suppression of BRD1 or MYOG led to downregulation of select EMT-associated genes, suggesting that RMS migration co-opts partial EMT-like transcriptional programs while retaining a differentiated myogenic identity. Together, these data define a previously unrecognized regulatory circuit in which BRD1 promotes a MYOG-driven, differentiation-associated migratory state. These findings challenge the prevailing paradigm that metastatic competence requires dedifferentiation and instead support a model in which a committed myogenic state actively drives RMS dissemination. Ongoing studies are focused on defining downstream effectors and evaluating the therapeutic vulnerability of this axis. Targeting BRD1-dependent transcriptional programs may represent a novel strategy to suppress metastasis in this aggressive pediatric cancer. Andrea D. Largent, Yadong Wang, Abraham Hengyucius, Umneya Alshaikhli, Lin Xu, Eleanor Chen. A differentiation-driven migration program in rhabdomyosarcoma (RMS) is governed by a BRD1-MYOG transcriptional axis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr B042.