Oncometabolites have garnered attention as detectable, targetable drivers of pathogenesis in several cancers. However, the variability of the metabolic landscape between tumors underscores a need for context-specific exploration. Natarajan and colleagues set out to address this in ZFTA–RELA fusion ependymomas, a subtype of malignant brain tumors with limited therapeutic opportunities. The authors first conducted unbiased metabolic screening using isogenic mouse neuronal stem cells (mNSCs) harboring a ZFTA–RELA fusion protein or an empty vector control. Compared with non-fusion cells, ZFTA–RELA+ mNSCs produced high levels of itaconate, an immunomodulatory metabolite with a poorly characterized role in tumor progression. Further mechanistic studies revealed that this increase was partially attributable to ZFTA–RELA-dependent upregulation of the itaconate catalyst cis-aconitate decarboxylase 1 (ACOD1). In order to examine the functional consequences of these findings, ZFTA–RELA ependymomas were established in Acod1WT and Acod1 conditional knockout mice using in utero electroporation (IUE). Interestingly, tumor-restricted Acod1 knockout was sufficient to significantly improve survival. Metabolic or pharmacologic ACOD1 inhibition yielded similar tumor suppression phenotypes, further emphasizing a pathogenic role for itaconate in ZFTA–RELA ependymomas. In addition to ACOD1 upregulation, initial metabolomic and isotope tracing studies indicated that elevated glutamine metabolism also contributes to itaconate production in ZFTA–RELA mNSCs. As expected, ZFTA–RELA tumors were therefore highly sensitive to the glutamine antagonist JHU-083, with potent tumor suppression observed in both IUE and patient-derived xenograft mouse models. Mechanistically, ZFTA–RELA influenced glutamine metabolism by increasing H3K27me3 levels, leading to transcriptional repression of PTEN and activation of downstream PI3K–AKT–mTOR signaling cascades that regulate expression of glutaminase and the glutamine transporter SLC1A5. It is also important to note that, while itaconate production occurred in a ZFTA–RELA-dependent manner, ZFTA–RELA expression was also epigenetically influenced by itaconate levels, indicating a feed-forward loop between the fusion oncoprotein and candidate oncometabolite. This study not only identifies itaconate as a biomarker for ZFTA–RELA-driven ependymomas but also provides important insight into the causes and effects of its upregulation in this context.Natarajan et al., 2026 Natarajan SK, Lum J, Skeans JH, Nenwani M, Eyunni S, Mota M, et al. ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression. Nature 2026 Feb 4 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.
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