Secreted Clusterin Inhibits Tumorigenesis by Modulating Tumor Cell and Macrophage in Human Meningioma.

BACKGROUND: Meningioma is the most common primary intracranial tumor with high frequency of postoperative recurrence, yet the biology of 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 animal model and cellular level.

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 I interferon pathway dependent on its secreted isoform, and the inhibition effect was enhanced by TNFα as TNFα also induced type I interferon pathway. The expression of CLU was upregulated by histone deacetylase inhibition. Meanwhile, both intra- and extra-cellular CLU overexpression enhanced macrophage polarization towards M1 phenotype and TNFα production, thus promoted tumor killing and phagocytosis.

CONCLUSIONS: CLU might be a key brake of meningioma malignance by synchronous modulating tumor cells and their microenvironment. Our work provides comprehensive insights into meningioma malignancy and a potential therapeutic strategy.