Secreted Clusterin Inhibits Tumorigenesis by Modulating Tumor Cell and Macrophage in Human Meningioma
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ABSTRACT:
PROVIDER: PRJNA851709 | ENA |
REPOSITORIES: ENA
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Project description:Our single-cell transcriptomic dataset exceeds the scale of previous efforts to systematically characterize meningioma. We identified CLU is tumor suppresser, also promote the anti-tumor capability of macrophage, that why CLU decreased in meningioma malignancy. HDACi may inhibit meningioma by increasing CLU expression. Therefore, promoting CLU expression maybe a great strategy for meningioma therapeutics.
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Project description:BackgroundMeningioma 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.MethodsTo 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.ResultsComprehensive 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.ConclusionsCLU 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.
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Project description:The conserved human secreted glycoprotein Clusterin (aka Apolipoprotein-J, ApoJ) is an abundant component of body fluids such as blood plasma and cerebrospinal fluid. Clusterin is thought to function as an extracellular molecular chaperone stabilizing misfolded proteins in solution. In addition, Clusterin forms lipoprotein complexes and fractions with HDL particles in plasma. Variants of the Clusterin gene constitute the third most important genetic risk factor for late-onset Alzheimer's disease. To better understand its structure and functions, the crystal structure of a mutant form of Clusterin was determined. In order to validate the structural data, hydrogen-deuterium exchange kinetics followed by pepsin proteolysis and mass spectrometry analysis of recombinant mutant and wildtype protein were performed (Part 1 of the deposited data). Based on the structure, rational mutants were designed and subjected to functional tests such as chaperone activity, cellular uptake and receptor binding and lipoprotein complex formation. In order to probe the conformation of Clusterin in the lipoprotein complex, free and lipid-bound protein were subjected to limited proteolysis with chymotrypsin and the resultant fragments analyzed by LC/MS proteomics (Part 2 of the deposited data).
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