A Primary Cell and Organoid Platform for Evaluating Pharmacological Responses in Mammary Epithelial Cells

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.