Abstract
Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer 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. SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy.See related commentary by Affronti and Wellen, p. 1161.This article is highlighted in the In This Issue feature, p. 1143.
Highlights
Glioblastoma is the most prevalent primary intrinsic brain tumor in adults, has a median survival of less than 15 months, and is universally lethal despite maximal therapy [1]
To identify glioma stem cells (GSC)-specific superenhancers in an unbiased manner, we utilized an in silico superenhancer target selection strategy to identify superenhancer-associated genes present within glioblastoma surgical specimens that overlapped with stem state–specific enhancers (Fig. 1A)
We focused on superenhancers specific to glioblastoma compared with normal brain samples (Fig. 1E)
Summary
Glioblastoma is the most prevalent primary intrinsic brain tumor in adults, has a median survival of less than 15 months, and is universally lethal despite maximal therapy [1]. There has been controversy surrounding the origins and defining molecular characteristics of cancer stem cells, functionally defined glioma stem cells (GSC) promote glioblastoma pathogenesis and contribute to the suboptimal efficacy of current treatment options through mediating angiogenesis [3], resistance to radiotherapy [4] and chemotherapy [5], invasion into normal brain [6], and self-renewal [7]. These characteristics implicate GSCs as important targets for the design of novel therapeutics for glioblastoma. We hypothesized that interrogation of superenhancer profiles may provide insight into the cell type–specific molecular processes that underlie GSC maintenance, identify cancer dependency genes and genetic programs critical to glioma initiation and progression, and translate into new therapeutic strategies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
