ID #496 Harnessing lipid metabolic reprogramming as a vulnerability in atypical teratoid/rhabdoid tumors
Stefania Tocci, Tessa O House, Marissa Coppola, Sofia Krykunenko, Jessica TsaiAbstract
Background
Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive pediatric brain tumors. Current therapies are associated with significant morbidity and toxicities, highlighting the need for novel treatment strategies. Tumor cells undergo metabolic transformations, including altered lipid metabolism, that drive tumor growth through increased lipid accumulation and energy production. Lipid metabolic pathways can be targeted by pharmacologic inhibition, making them attractive targets. While lipid metabolic reprogramming is a hallmark of cancer, it is unknown whether it plays a role in AT/RT.
Methods
Using in vitro patient-derived AT/RT models, functional genomics, pharmacologic inhibition, RNA-sequencing, ChIP-sequencing, metabolic assays, and in silico analysis we sought to test whether lipid metabolism represents a unique dependency in AT/RT and whether it can be exploited as a therapeutic target.
Results
We analyzed RNA-sequencing expression data from pediatric brain tumor cell lines and performed enrichment analysis of lipid metabolic genes. AT/RT cells exhibit significantly increased expression of genes involved in de novo lipogenesis, suggesting these pathways may represent unique vulnerabilities in AT/RT. Specifically, Stearoyl-CoA Desaturase (SCD), an enzyme that converts saturated fatty acids into monounsaturated acids, is uniquely elevated in AT/RT compared to other tumor types. CRISPR/Cas9-mediated knockout of SCD in patient-derived AT/RT neurospheres resulted in a significant attenuation of cell viability and neurosphere formation. Rescue experiments using fatty acids following SCD inhibition will determine whether the observed phenotype is specifically attributable to the disruption of the SCD pathway. Transcriptomic and metabolomic profiling are currently underway to elucidate transcriptional and metabolic changes mediated by SCD. Furthermore, we are testing clinically available SCD inhibitors to assess their efficacy in AT/RT cells. Ongoing ChIP-sequencing for SREBF1, master transcriptional regulator of lipid metabolism, will map chromatinbinding sites and define the transcriptional lipid regulation at the chromatin level.
Conclusion
Lipid metabolism is deranged in AT/RT and represents a potential therapeutic target.