Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We recreate this infiltrative microenvironment in vitro based on resected patient tumors and examine malignancy metrics (invasion, proliferation, and stemness) in the context of cellular and biophysical factors and therapies. Our 3D tissue-engineered model comprises patient-derived glioma stem cells, human astrocytes and microglia, and interstitial fluid flow. We found flow contributes to all outcomes across seven patient-derived lines, and glial effects are driven by CCL2 and differential glial activation. We conducted a six-drug screen using four outcomes and find expression of putative stemness marker CD71, opposed to viability IC50, significantly predicts murine xenograft survival. Our results dispute the paradigm of viability as predictive of drug efficacy. We posit this patient-centric, infiltrative tumor model is a novel advance towards translational personalized medicine.

中文翻译：

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浸润性胶质母细胞瘤微环境的患者设计的组织工程模型

胶质母细胞瘤是一种以弥漫性浸润为特征的侵袭性脑癌。浸润的神经胶质瘤细胞在切除后仍保留在大脑中，在那里它们与神经胶质细胞相互作用并经历间质液流动。我们基于切除的患者肿瘤在体外重建这种浸润性微环境，并在细胞和生物物理因素及疗法的背景下检查恶性指标（侵袭，增殖和干性）。我们的3D组织工程模型包含患者来源的神经胶质瘤干细胞，人类星形胶质细胞和小胶质细胞以及间质液流动。我们发现血流有助于跨越七个患者来源的谱系的所有结局，并且胶质细胞的作用受CCL2和差异性胶质细胞激活的驱动。我们使用四个结果进行了六药筛查，发现了假定的干性标记CD71的表达，与生存力IC50相反，它可以显着预测鼠类异种移植物的存活。我们的研究结果质疑了生存范式可预测药物疗效。我们认为这种以患者为中心的浸润性肿瘤模型是朝着转化个性化医学的新进展。