SMARCB1 Loss in Poorly-differentiated Chordomas Drives Tumor Progression

Poorly-differentiated (PD) chordoma, a tumor found mainly in children, adolescents and young adults is a rare, aggressive tumor originating from notochordal tissue, with limited therapeutic options. SMARCB1, a core component of the BAF and PBAF chromatin remodeling complexes, is the most frequently mutated gene in PD chordomas, the most aggressive form of this cancer. In this study, we employed cellular models of SMARCB1-negative PD chordomas to characterize expression of SWI/SNF complex members and determine the impact of SMARCB1 re-expression on cell growth as well as the transcriptional landscape by RNA-seq. We generated 2 SMARCB1-negative PD chordoma cell lines, CH22 and UM-Chor5, with an inducible SMARCB1 expression system. After 72 hours of induction of SMARCB1 re-expression, we observed continued growth of both SMARCB1-negative PD chordoma cell lines. This is in striking contrast to SMARCB1-deficient rhabdoid cell lines, where we found SMARCB1 re-expression inhibits growth completely. We also found the lack of growth inhibition may arise from the loss of CDKN2A/p16INK4A expression in all poorly differentiated chordoma cell lines which correlated well with the gene expression data. SMARCB1 re-expression in both CH22 and UM-Chor5 cells showed downregulation for rRNA and RNA processing as well as metabolic processing. Upregulated differentially expressed genes included those involved in cell adhesion, cell migration, and development. Taken together, our data establish SMARCB1 re-expression in PD chordomas alters the repertoire of SWI/SNF complexes, perhaps restoring those associated with cellular differentiation. Our findings support a model where SMARCB1 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones. RNA-seq of various chordoma and malignant rhabdoid tumor (MRT) cell lines with and without the addition of SNF5 (SMARCB1).