Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain’s metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour.

中文翻译：

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肿瘤微环境的星形胶质细胞免疫代谢调节驱动胶质母细胞瘤的致病性

恶性脑肿瘤是癌症患者发病率和死亡率不成比例的原因，这一不幸的统计数据几十年来一直保持不变。尽管在这些肿瘤的分子特征方面取得了相当大的进步，但靶向癌细胞的治疗尚未取得重大进展。另一种策略是靶向胶质母细胞瘤微环境中的细胞，例如肿瘤相关星形胶质细胞。星形胶质细胞控制健康和疾病的多个过程，从维持大脑的代谢稳态到调节神经炎症。然而，它们在胶质母细胞瘤致病性中的作用尚不清楚。在这里，我们报告反应性星形胶质细胞的耗竭使胶质母细胞瘤消退并延长小鼠存活期。对肿瘤相关星形胶质细胞翻译组的分析表明，星形胶质细胞启动了转录程序，这些程序塑造了神经胶质瘤微环境中的免疫和代谢区室。具体而言，它们表达的 CCL2 和 CSF1 控制肿瘤相关巨噬细胞的募集并促进促肿瘤巨噬细胞表型。同时，我们证明星形胶质细胞衍生的胆固醇是神经胶质瘤细胞存活的关键，并且通过 ABCA1 靶向星形胶质细胞胆固醇流出，阻止肿瘤进展。总之，星形胶质细胞通过重新编程肿瘤微环境的免疫学特性和支持胶质母细胞瘤对胆固醇的非致癌代谢依赖性来控制胶质母细胞瘤的致病性。