Glioblastoma is the most common and deadly form of primary brain cancer, accounting for more than 13,000 new diagnoses annually in the USA alone. Microglia are the innate immune cells within the central nervous system, acting as a front-line defense against injuries and inflammation via a process that involves transformation from a quiescent to an activated phenotype. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy. This work used a brain-mimetic hydrogel system to study patient-derived glioblastoma specimens and their interactions with microglia. Here, glioblastoma cells were either cultured alone in 3D hydrogels or in co-culture with microglia in a manner that allowed secretome-based signaling but prevented direct GBM-microglia contact. Patterns of GBM cell invasion were quantified using a three-dimensional spheroid assay. Secretome and transcriptome (via RNAseq) were used to profile the consequences of GBM-microglia interactions. Microglia displayed an activated phenotype as a result of GBM crosstalk. Three-dimensional migration patterns of patient-derived glioblastoma cells showed invasion was significantly decreased in response to microglia paracrine signaling. Potential molecular mechanisms underlying with this phenotype were identified from bioinformatic analysis of secretome and RNAseq data. The data demonstrate a tissue engineered hydrogel platform can be used to investigate crosstalk between immune cells of the tumor microenvironment related to GBM progression. Such multi-dimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.

中文翻译：

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小胶质细胞和患者来源的胶质母细胞瘤细胞之间的串扰抑制三维明胶水凝胶模型中的侵袭


胶质母细胞瘤是最常见和最致命的原发性脑癌，仅在美国每年就有超过 13,000 例新诊断病例。小胶质细胞是中枢神经系统内的先天免疫细胞，通过从静止表型转变为激活表型的过程，充当抵御损伤和炎症的前线防御细胞。 GBM 细胞和小胶质细胞之间的串扰是开发组织工程平台时需要考虑的重要轴，以检查 GBM 进展和治疗的病理生理过程。这项工作使用仿脑水凝胶系统来研究患者来源的胶质母细胞瘤标本及其与小胶质细胞的相互作用。在这里，胶质母细胞瘤细胞要么在 3D 水凝胶中单独培养，要么与小胶质细胞共培养，其方式允许基于分泌组的信号传导，但阻止 GBM-小胶质细胞直接接触。使用三维球体测定对 GBM 细胞侵袭的模式进行量化。分泌组和转录组（通过 RNAseq）用于分析 GBM-小胶质细胞相互作用的后果。由于 GBM 串扰，小胶质细胞表现出激活的表型。患者来源的胶质母细胞瘤细胞的三维迁移模式显示，响应小胶质细胞旁分泌信号传导，侵袭显着减少。通过分泌蛋白组和​​ RNAseq 数据的生物信息学分析，确定了该表型的潜在分子机制。数据表明，组织工程水凝胶平台可用于研究与 GBM 进展相关的肿瘤微环境的免疫细胞之间的串扰。这种多维模型可以提供有价值的见解，为改善 GBM 治疗的治疗创新提供信息。