The role and mechanism of necrosis in glioblastoma

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Project Summary Gliomas are major primary brain tumors, of which glioblastomas (GBM) are the most common and aggressive forms. The poor outcome of traditional treatment for these tumors demands targeted therapies based on identified mechanisms that drive tumor development. Molecular pathology has classified GBM into subtypes, among which the mesenchymal (MES) group is the most malignant. It is still unclear how GBM MES differentiation is achieved. Recent anatomically based transcriptome studies found that tumor cells associated with the necrotic region have higher expression of the MES signature genes, suggesting that the necrotic tumor microenvironment may contribute to MES differentiation and could be exploited as a therapeutic target. The goal of this project is to mechanistically and functionally study GBM necrosis, and identify vulnerabilities of GBM MES progression for therapeutics. We have established the follow premise for the proposed studies. First, we have developed novel pathologically relevant GBM mouse models showing MES differentiation and extensive necrosis. Second, we identified ferroptosis as a novel mechanism for GBM necrosis. Third, in both patient GBM samples and mouse models, we found that the necrotic tumor areas are infiltrated by neutrophils. Our studies suggested that these tumor-associated neutrophils (TANs) are necessary and sufficient to induce tumor cell ferroptosis. Furthermore, we found that ferroptosis and TANs are associated with the hypoxic tumor microenvironment. We hypothesize that GBM necrosis occurs through neutrophil-triggered ferroptosis, and this process is orchestrated by the hypoxic tumor microenvironment. We further hypothesize that ferroptosis could promote tumor progression and be targeted for therapeutic purposes. We propose the following three specific aims: 1) to determine the mechanism of tumor cell ferroptosis induced by TANs; 2) to determine the role of hypoxic tumor microenvironment in tumor cell ferroptosis; 3) to demonstrate the role of ferroptosis in GBM progression and evaluate therapeutic effects of ferroptosis blockade. We will employ a panel of established human GBM cell lines, newly isolated human GBM cells, and mouse GBM models. GBM necrosis is a diagnostic hallmark, predicts tumor aggressiveness, and has deleterious effects on treatments. The nature and mechanism of cell death associated with this necrosis remain obscure. In addition, whether tumor necrosis blockade could benefit therapies is still unknown. By establishing the GBM models faithfully recapitulating the extent of necrosis observed in GBM patients and identification of ferroptosis as the underlying mechanism of tumor necrosis, this proposal will reveal vulnerabilities of GBM MES progression, which could be a novel avenue for GBM therapeutics.