A proteogenomic RNA processing mechanism drives sex differences in meningioma

Meningiomas are the most common primary intracranial tumors and the only brain tumors that are more common in females compared with males1. Progestin hormonal therapies increase the risk of meningioma, and progestin-induced or pregnancy-associated meningiomas can regress as serum progestogen levels normalize2. The mechanisms that underlie sex differences and progestogen signaling in meningioma are unknown. Here we show that sex hormone interaction with PGRMC1, a transmembrane progesterone binding protein, regulates the activity of RNA processing proteins FXR1 and RBM39 to drive meningioma sex differences. The genomic architecture and stem cells underlying meningiomas are conserved across vertebrate species3-5 and, using mass spectrometry-based proteomics to analyze 703 meningioma and meningeal samples, we demonstrate that meningiomas are enriched in RNA processing proteins in humans and dogs. Interactions between PGRMC1, FXR1, and RBM39 are inhibited by progestogens and stabilized by testosterone. After release from PGRMC1, FXR1 and RBM39 bind and stabilize progesterone receptor (PR) transcript to enable expression of PR protein, which induces cell cycle, membrane, and cytoskeleton remodeling genes that drive tumor growth. These findings reveal therapeutic strategies and a PR target gene biomarker that may improve outcomes for patients. More broadly, we elucidate an estrogen receptor-independent mechanism of PR expression that underlies sex differences in cancer.