Organoid cultures are widely used for tumor modeling because they preserve many phenotypic features of cancer cells in vivo. However, current organoids present issues of consistency, efficiency, mimicry, and cell-seeding control. More importantly, they can only contain only one extracellular matrix (ECM) compartment at a time, while solid tumors feature two main ECM compartments: the basement membrane and the stromal matrix. Here, we develop, test, and validate a high-throughput oil-in-water droplet microtechnology to generate highly uniform, small-volume, multi-compartment organoids. Each organoid culture features microenvironmental architectures that mimic both the basement membrane and stromal barriers. This matrix architecture, which allows us to simultaneously take into account and assess the proliferative and invasive properties of cancer cells in a single platform, has profound effect on observed drug responsiveness and tumor progression that correlate well with in vivo and clinical outcomes. Our method was tested on multiple types of cells including primary breast and ovarian cancer cells and immortalized cell lines, and we determined our platform is suitable even for cancer cells of poor standard organoid-forming ability such as primary patient samples. These new organoids also allow for direct orthotopic mouse implantation of cancer cells with unprecedented success.

Multi-compartment tumor organoids

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DOI: 10.1016/j.mattod.2022.07.006