Glioma Stem Cell Specific Super Enhancer Drives Polyunsaturated Fatty Acid Synthesis to Support EGFR Signaling

Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSCs) contribute to this poor prognosis by driving therapeutic resistance and maintenance of cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the super-enhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs. Overall design: Two patient-derived glioma stem cells (GSC387 and GSC3565) were transduced with two independent non-overlapping shRNAs targeting ELOVL2 (shELOVL2.308 and shELOVL2.843) or a non-targeting control shRNA (shCONT). 6 total samples were analyzed with 1 technical replicate per group