An essential process in predicting the in vivo pharmacological activity of a candidate molecule involves the evaluation of target responses using established model systems. While these models largely comprise immortalized cells, which are often serially passaged as monolayers on uniformly stiff substrates and are modified to overexpress one or more components of the pathway-of-interest, the importance of cell identity, heterogeneity, and three-dimensional (3D) context to target response is gaining increasing attention. Here, we assess intracellular calcium responses in mouse mammary epithelial cells in three distinct model systems: 3D primary organoids, 2D primary epithelial cells, and 2D immortalized cells. Specifically, we assess intracellular calcium responses to a number of extracellular signals implicated in the regulation of basal (or myoepithelial) cell function. These findings provide further insights into cell type and context-specific pharmacological responses in mammary epithelial cells and highlight the opportunities and challenges in the adoption of architecturally complex and heterogeneous in vitro assays in pharmacological research.

中文翻译：

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评价乳腺上皮细胞药理反应的主要细胞和类器官平台

体内预测的基本过程候选分子的药理活性涉及使用已建立的模型系统评估靶标反应。尽管这些模型主要包含永生化细胞，但它们通常以单层的形式连续传代在均匀坚硬的基质上，并经过修饰以过表达感兴趣途径的一个或多个组成部分，细胞同一性，异质性和三维（3D）的重要性）针对目标响应的环境越来越受到关注。在这里，我们在三种不同的模型系统中评估小鼠乳腺上皮细胞的细胞内钙反应：3D初级类器官，2D初级上皮细胞和2D永生化细胞。具体来说，我们评估细胞内钙对许多涉及基础（或肌上皮）细胞功能调节的细胞外信号的反应。药理研究中的体外测定。