3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient‐derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide‐functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient‐derived xenograft cells. The in vitro behavior of 3 patient‐derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix‐immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix‐immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.

中文翻译：

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细胞外透明质酸影响胶质母细胞瘤生物材料模型中 EGFR 酪氨酸激酶抑制剂的功效

3D 生物材料模型有潜力利用患者来源的细胞探索肿瘤微环境对异常信号通路和补偿信号的影响。胶质母细胞瘤（GBM）肿瘤具有高度异质性，细胞组成和细胞外基质生物物理因素被视为恶性表型和治疗结果的关键调节因素。50% 的 GBM 患者中已发现表皮生长因子受体 (EGFR) 酪氨酸激酶的扩增、过度表达和突变。在这里，透明质酸 (HA) 装饰的甲基丙烯酰胺功能化明胶 (GelMA) 水凝胶用于使用患者来源的异种移植细胞检查微环境因素和模型 EGFR 酪氨酸激酶抑制剂 (TKI) 之间的协同作用。3 种源自患者的异种移植物的体外行为反映了临床相关的 EGFR 变异范围：GBM10（EGFR，野生型）、GBM12（EGFR+）和 GBM6（EGFRvIII）。GelMA 水凝胶支持异种移植培养；细胞保持活力、活跃，对基质固定的 HA 做出反应，并上调与基质重塑和肿瘤生长相关的基因。有趣的是，基质固定的 HA 改变了 GBM 细胞对模型酪氨酸激酶抑制剂厄洛替尼的反应。虽然组成型激活的 EGFRvIII 细胞对明胶水凝胶中的 TKI 敏感，但透明质酸介导的粘附信号传导与 EGFRvIII 信号传导相互作用，以增加细胞代谢活性，增加可溶性透明质酸合成，并改变对厄洛替尼暴露的反应。