KEY TAKEAWAYS
- The study aimed to seek therapeutic targets for recurrent meningiomas, addressing challenges posed by limited metabolism understanding and treatment options.
- The study concluded that targeting the GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas offers a promising new therapeutic avenue.
Brain cancer, particularly meningiomas, constitutes the most prevalent form of brain tumors, yet recurrent malignant types present dismal prognosis. Despite being commonly benign, atypical and anaplastic meningiomas often recur with poor outcomes. The metabolic intricacies of meningiomas remain poorly understood, limiting treatment options predominantly to surgery and radiation, while targets for recurrence management remain undefined.
Kiyotaka Yokogami and the team conducted a study that aimed to identify therapeutic targets for meningioma recurrence, addressing limited understanding of their metabolism and treatment options.
The study investigated the effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and the upstream regulator Gremlin2 (GREM2) on meningioma growth and senescence. Proliferation assays assessed BMP signaling inhibition, while forced GREM2 expression was comprehensively analyzed.
The correlations between GREM2 mRNA expression and proliferation markers were studied in 87 clinical samples. Enrichment analysis between GREM2 expression groups used RNA-seq data (42 cases) from the GREIN database. Changes in metabolites and senescence markers associated with BMP signal suppression were also examined.
The results demonstrated that inhibitors targeting the BMP receptor (BMPR1A) and forced expression of GREM2 altered tryptophan metabolism in malignant meningiomas, favoring serotonin production over kynurenine/quinolinic acid production. This shift was accompanied by reduced NAD+/NADH production and decreased expression of gene clusters related to oxidative phosphorylation, leading to a decrease in ATP levels.
The malignant meningiomas exhibited cellular senescence, decreased proliferation, and the eventual formation of psammoma bodies. Reanalysis of RNA-seq data from clinical samples obtained from the GREIN database revealed that increased GREM2 expression was associated with decreased expression of genes involved in oxidative phosphorylation, consistent with the experimental findings.
The study concluded that targeting the GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas presents a promising novel therapeutic approach.
Funding for open access was provided by the University of Miyazaki. This research received support from JSPS KAKENHI, a Grant for Clinical Research from Miyazaki University Hospital (K.Y.), also grants from Otsuka and Chugai.
Source: https://link.springer.com/article/10.1007/s11060-024-04625-2
Yokogami, K., Watanabe, T., Yamashita, S. et al. “Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma.” J Neurooncol (2024). https://doi.org/10.1007/s11060-024-04625-2.
