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Advanced Development of Primary Pancreatic Organoid Tumor Models forHigh-Throughput Phenotypic Drug Screening

机译：胰腺原发性类器官肿瘤模型的高级开发高通量表型药物筛选

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Traditional high-throughput drug screening in oncology routinely relies on two-dimensional (2D) cell models, which inadequately recapitulate the physiologic context of cancer. Three-dimensional (3D) cell models are thought to better mimic the complexity of in vivo tumors. Numerous methods to culture 3D organoids have been described, but most are nonhomogeneous and expensive, and hence impractical for high-throughput screening (HTS) purposes. Here we describe an HTS-compatible method that enables the consistent production of organoids in standard flat-bottom 384- and 1536-well plates by combining the use of a cell-repellent surface with a bioprinting technology incorporating magnetic force. We validated this homogeneous process by evaluating the effects of well-characterized anticancer agents against four patient-derived pancreatic cancer KRAS mutant-associated primary cells, including cancer-associated fibroblasts. This technology was tested for its compatibility with HTS automation by completing a cytotoxicity pilot screen of ~3300 approved drugs. To highlight the benefits of the 3D format, we performed this pilot screen in parallel in both the 2D and 3D assays. These data indicate that this technique can be readily applied to support large-scale drug screening relying onclinically relevant, ex vivo 3D tumor models directly harvested from patients,an important milestone toward personalized medicine.
机译：肿瘤学中传统的高通量药物筛查通常依赖于二维（2D）细胞模型，该模型无法充分概括癌症的生理情况。人们认为三维（3D）细胞模型可以更好地模拟体内肿瘤的复杂性。已经描述了许多培养3D类器官的方法，但是大多数方法不均一且昂贵，因此对于高通量筛选（HTS）的目的是不切实际的。在这里，我们描述了一种与HTS兼容的方法，该方法通过结合使用细胞排斥表面和结合了磁力的生物打印技术，能够在标准的平底384和1536孔板上连续生产类器官。我们通过评估特征明确的抗癌药对四种患者来源的胰腺癌KRAS突变体相关的原代细胞，包括与癌症相关的成纤维细胞的作用，验证了这一均一的过程。通过完成约3300种批准药物的细胞毒性试验筛选，测试了该技术与HTS自动化的兼容性。为了突出3D格式的好处，我们在2D和3D分析中并行执行了该试验屏幕。这些数据表明，该技术可以很容易地应用于支持依赖于临床相关的直接从患者体内收集的离体3D肿瘤模型，个性化医学的重要里程碑。

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