Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment.

脑肿瘤是具有多种细胞类型的动态复杂生态系统。为了在可重复和可扩展的系统中模拟脑肿瘤微环境，我们开发了一种快速三维（3D）生物打印方法来构建临床相关的仿生组织模型。在复发性胶质母细胞瘤中，巨噬细胞/小胶质细胞对肿瘤块有显着贡献。为了解析巨噬细胞的 3D 功能，我们比较了胶质母细胞瘤干细胞 (GSC) 单独的生长或与星形胶质细胞和神经前体细胞在富含透明质酸的水凝胶中（有或没有巨噬细胞）的生长情况。整合巨噬细胞的生物打印构建体概括了患者来源的转录谱，可预测患者的生存、干细胞的维持、侵袭和耐药性。使用生物打印的复杂系统进行全基因组 CRISPR 筛选，确定了 GSC 中相对于球体培养的独特分子依赖性。多细胞生物打印模型作为一个可扩展的生理学平台，用于研究药物敏感性、细胞串扰、入侵、特定环境的功能依赖性以及物种匹配的神经环境中的免疫相互作用。