Induced senescence and calcification in anaplastic meningioma

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Abstract Purpose. Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target. Methods. This study focused on meningioma metabolism and demonstrated that bone morphogenetic protein (BMP) signaling regulates meningioma growth, cellular senescence, and calcification. Results. Inhibitors of BMP receptor (BMPR1A) and forced expression of Gremlin2 (GREM2) shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD+/NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. We reanalyzed RNA-sequencing data of clinical samples obtained from GEO RNA-seq Experiments Interactive Navigator, a public database, and found that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results. Conclusions. The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target.

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