Background Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO high TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCO high TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

中文翻译：

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在间充质胶质母细胞瘤中驱动恶性的肿瘤相关巨噬细胞的转录调控网络

背景 胶质母细胞瘤 (GBM) 是一种复杂的疾病，具有广泛的分子和转录异质性。GBM 可细分为四种不同的亚型；复发后转变为间充质表型的肿瘤通常与治疗抵抗、不良预后和促肿瘤巨噬细胞浸润有关。结果 我们探索了间充质相关肿瘤相关巨噬细胞 (MA-TAM) 的转录调控网络，其驱动了 GBM 的恶性表型状态，并将具有胶原结构的巨噬细胞受体 (MARCO) 鉴定为差异表达最高的基因。MARCO 高 TAM 诱导神经胶质瘤干细胞向间充质细胞状态的表型转变，促进侵袭和增殖活动，以及对辐射的治疗抵抗。MARCO 高 TAM 还显着加速体内肿瘤的植入和生长。此外，MA-TAM 主调节因子及其靶基因都与不良的临床结果显着相关，并且通常与神经纤维蛋白 1 (NF1) 和磷酸肌醇 3-激酶/雷帕霉素/Akt 通路的哺乳动物靶标 (PI3K-mTOR- AKT) 相关基因。我们进一步证明了 MA-TAMs 来自外周血，以及它们与肿瘤诱导的极化状态和免疫抑制环境的潜在关联。结论 总的来说，我们的研究表征了驱动间充质 GBM 发病机制的 TAM 的全局转录谱，为提高 GBM 免疫治疗的有效性提供了潜在的治疗靶点。