Secreted clusterin inhibits tumorigenesis by modulating tumor cells and macrophages in human meningioma

Abstract Background Meningioma is the most common primary intracranial tumor with a high frequency of postoperative recurrence, yet the biology of the meningioma malignancy process is still obscure. Methods To identify potential therapeutic targets and tumor suppressors, we performed single-cell transcriptome analysis through meningioma malignancy, which included 18 samples spanning normal meninges, benign and high-grade in situ tumors, and lung metastases, for extensive transcriptome characterization. Tumor suppressor candidate gene and molecular mechanism were functionally validated at the animal model and cellular levels. Results Comprehensive analysis and validation in mice and clinical cohorts indicated clusterin (CLU) had suppressive function for meningioma tumorigenesis and malignancy by inducing mitochondria damage and triggering type 1 interferon pathway dependent on its secreted isoform, and the inhibition effect was enhanced by TNFα as TNFα also induced type 1 interferon pathway. Meanwhile, both intra- and extracellular CLU overexpression enhanced macrophage polarization towards M1 phenotype and TNFα production, thus promoting tumor killing and phagocytosis. Conclusions CLU might be a key brake of meningioma malignance by synchronously modulating tumor cells and their microenvironment. Our work provides comprehensive insights into meningioma malignancy and a potential therapeutic strategy.