Abstract
Chordomas are rare, aggressive tumors of the axial skeleton with limited treatment options. Genetic alterations in SMARCB1, a tumor suppressor gene, have been implicated in poorly differentiated chordomas, but their role in typical and chondroid subtypes remains unclear. This study examined 42 chordoma samples (26 typical, 16 chondroid) for SMARCB1 genetic alterations, expression patterns, and associated pathways. SMARCB1 knockdown experiments were conducted in chordoma cell lines, followed by comprehensive transcriptome analysis. No exonic SMARCB1 mutations were identified, but heterozygous loss was observed in 3/26 typical chordomas. SMARCB1 expression positively correlated with patient survival and epithelial-mesenchymal markers. Functional studies revealed that SMARCB1 knockdown significantly enhanced cell proliferation, migration, and invasion. Transcriptome analysis demonstrated enrichment of MYC targets, E2F targets, and cell cycle pathways in SMARCB1-low samples, while cellular adhesion pathways were downregulated. Notably, SLPI, LBH, and LOXL2 were significantly downregulated in SMARCB1-low samples. SMARCB1 plays an important role in chordoma progression, influencing prognosis and cellular behavior, despite infrequent genetic alterations. Its effects on key oncogenic pathways and cellular plasticity suggest potential for targeted therapies. These findings provide new insights into chordoma biology and lay the groundwork for developing SMARCB1-based prognostic tools and personalized treatment strategies.