STEM-10. SUPER-ENHANCER SCREEN IDENTIFIES LIPID METABOLISM AS A CANCER STEM CELL DEPENDENCY IN GLIOBLASTOMA

Super-enhancer screen identifies lipid metabolism as a cancer stem cell dependency in glioblastoma Ryan C. Gimple, Stephen C. Mack, Jeremy N. Rich Glioblastoma is the most prevalent and aggressive primary intrinsic brain tumor in adults and is among the most lethal of all human cancers with poor responses to all therapeutic modalities. Functionally defined glioma stem cells (GSCs) are proposed to contribute to this poor prognosis by mediating therapy resistance, self-renewal, and maintenance of cellular heterogeneity. To understand the cell-type-specific molecular processes that underlie GSC maintenance and tumorigenicity, we profiled super-enhancers through analysis of active enhancer histone modification data (H3K27ac) in matched GSC and differentiated glioma cell (DGC) samples. Super-enhancers, defined as clusters of typical enhancers, function as master epigenetic regulators that define cell state, orchestrate cell-type dependent transcriptional networks, and drive key oncogenes in a variety of cancers. This approach revealed lipid biosynthesis as a potential epigenetically regulated GSC dependency pathway. Knockdown of a key lipid metabolism gene in patient-derived GSCs resulted in decreased cell proliferation, diminished self-renewal, and induction of apoptosis in vitro, as well as impaired tumor formation in vivo. In a validation cohort, patient derived GSC tumor models containing the identified super-enhancer exhibited high expression of the lipid metabolism gene, suggesting that the expression of this gene is epigenetically driven. Next, we analyzed the upstream transcription factor control circuits that underlie a critical super-enhancer in this pathway. Expression of two neurodevelopmental transcription factors, OLIG2 and SOX2, were found to be significantly positively correlated with that of a lipid metabolism gene in clinical samples, suggesting that occupancy of these factors may drive the persistence of this super-enhancer. This discovery implicates aberrant lipid metabolism networks in glioma pathogenesis and suggests that targeting of fatty acid synthesis may provide a specific way to more effectively treat patients with glioblastoma.