An Unexpected Metabolite Reveals a New Weakness in Ependymomas 

Ependymomas are rare tumors of the brain or spinal cord that occur in both children and adults (1). In the majority of ependymomas arising from the supratentorial brain region, zinc finger translocation associated (ZFTA), a chromatin remodeler, fuses with RELA, also known as p65, a mediator of NF-κB signaling, to create the potent oncogene ZFTA-RELA (2). It remains poorly understood how the ZFTA-RELA fusion protein drives tumor growth. Recent work published in Nature identifies itaconate as a candidate oncometabolite in ZFTA-RELA+ ependymomas. The study shows that these tumors undergo metabolic rewiring to produce itaconate, establishing a feed-forward loop that sustains ZFTA-RELA expression and promotes tumor growth (3). This was an unexpected finding, as itaconate is a metabolite typically made by macrophages in response to invading pathogens, and its production by tumor cells is far less explored (4). The findings reveal multiple druggable targets, opening potential avenues for treating this aggressive cancer. 

The work was led by Siva Kumar Natarajan, PhD, a postdoctoral fellow in the laboratories of Sriram Venneti, MD, PhD, and Arul Chinnaiyan, MD, PhD, at the University of Michigan. Dr. Natarajan received the 2025 AACR-Sontag Brain Cancer Research Fellowship to investigate the oncogenic role of itaconate in ZFTA-RELA fusion-driven ependymomas. Despite decades of research, surgery followed by radiation or sometimes chemotherapy remains the mainstay of treatment. “The existing treatments only prolong survival and do not cure these tumors,” Dr. Natarajan stated. He added that “our findings show that these ependymoma cells hijack a metabolic pathway previously described in immune cells. We have also identified multiple signaling and metabolic vulnerabilities in these tumors that can be therapeutically targeted.” This work provides new mechanistic insight into how ZFTA-RELA drives ependymoma progression and highlights a new avenue to develop targeted therapeutics for this cancer.

Reprogrammed metabolism is a hallmark of cancer (5), prompting the research team to investigate the metabolic dependencies of ZFTA-RELA+ ependymomas. They found that expression of the ZFTA-RELA fusion protein upregulated itaconate levels in mouse neuronal stem cells (mNSCs) and patient-derived ependymoma cell lines. Given that itaconate is produced by the enzyme aconitate decarboxylase (ACOD1), the team assessed ACOD1 protein levels and found that ACOD1 and ZFTA-RELA protein levels were positively correlated. Chemical inhibition of ACOD1 suppressed tumor growth and improved survival in ZFTA-RELA mouse models.

The researchers then investigated the molecular mechanisms underlying the positive correlation between ACOD1 and ZFTA-RELA protein levels. RNA-sequencing (RNA-seq) revealed a role for transcriptional regulation, as ZFTA-RELA mRNA levels decreased upon ACOD1 inhibition. Mechanistically, the authors showed that itaconate inhibits the H3K4 demethylase KDM5, thereby maintaining high levels of the activating histone mark H3K4me3. Mutation of putative KDM5 binding sites within the ZFTA regulatory region increased H3K4me3 enrichment in this region. This was accompanied by an increase in ZFTA-RELA and ACOD1 protein levels as well as increased proliferation in vitro and increased tumor growth in vivo. Overall, these data suggest that itaconate participates in a feed-forward mechanism to sustain ZFTA-RELA expression by preserving an active chromatin state at the ZFTA regulatory region, which further elevated ACOD1 expression to sustain itaconate levels.

Given itaconate’s key role in ZFTA-RELA+ tumor progression, the team interrogated the mechanisms behind the metabolite’s production. They found that ZFTA-RELA+ ependymomas upregulated glutamine metabolism to supply carbons for itaconate synthesis. Because PI3K-AKT signaling is a key regulator of glutaminolysis and is negatively regulated by the tumor suppressor protein PTEN, the team investigated PTEN expression. Interestingly, lower PTEN protein levels were observed in both mouse and human ZFTA-RELA+ ependymomas despite the absence of PTEN deletions or mutations, suggesting a key role for transcriptional repression. Indeed, ZFTA-RELA expression increased the repressive histone mark H3K27me3 at the Pten locus, resulting in reduced chromatin accessibility and suppression of PTEN expression. Analysis of published ependymoma single-cell RNA-seq datasets revealed that low PTEN expression was associated with higher SLC1A5 and GLS expression, which encode proteins responsible for glutamine uptake and metabolism, respectively. Patients with ZFTA-RELA+ ependymomas that exhibited this gene expression pattern had worse progression-free and overall survival.

Having identified key pathways involved in ZFTA-RELA+ ependymomas to sustain itaconate synthesis, the researchers tested a range of chemical inhibitors for therapeutic potential. Pharmacologic inhibition of glutamine metabolism, particularly with the CNS-penetrant glutamine antagonist JHU-083, significantly suppressed tumor growth and extended survival across several mouse models. Likewise, inhibition of ACOD1 reduced tumor progression and lowered ZFTA–RELA expression. Importantly, combination strategies inhibiting multiple nodes of this metabolic pathway, including ACOD1, glutamine metabolism, and PI3K-mTOR signaling, produced the strongest antitumor effects and prevented spinal metastases in vivo. These preclinical data demonstrate the potential of targeting glutamine metabolism and downstream itaconate pathways, either alone or in combination, as a therapeutic strategy.

“This grant has been instrumental in advancing my research and career,” Dr. Natarajan shared when reflecting on the impacts of receiving this fellowship. The work supported by this fellowship provided him with important visibility within the cancer research community and enabled him to present his findings at major scientific meetings, where they were met with strong enthusiasm. The research team is now working with clinical collaborators to translate these findings toward future clinical studies. “I strongly believe that this funding has been a catalyst in driving important milestones of my career,” he stated. Building on the discoveries made during the fellowship, he plans to pursue new research directions and ultimately establish a research program focused on addressing unmet needs in brain cancer, a field for which new treatment options are desperately needed.

References

1. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA,Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 2021;23(8):1231-1251. doi: 10.1093/neuonc/noab106.
2. Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, et al. C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 2014;506(7489):451-5. doi: 10.1038/nature13109.
3. 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;654(8111):1004-1015. doi: 10.1038/s41586-025-10005-1.
4. Li Z, Zheng W, Kong W, Zeng T. Itaconate: a potent macrophage immunomodulator Inflammation 2023;46(4):1177-1191. doi: 10.1007/s10753-023-01819-0.
5. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov 2022;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059.