Abstract
Three-dimensional cell culture platforms based on decellularised patient-based microenvironments provide in vivo-like growth conditions allowing cancer cells to interact with intact structures and components of the surrounding tissue. A patient-derived scaffold (PDS) model was therefore evaluated as a testing platform for the endocrine therapies (Z)-4-Hydroxytamoxifen (4OHT) and fulvestrant as well as the CDK4/6-inhibitor palbociclib, monitoring the treatment responses in breast cancer cell lines MCF7 and T47D adapted to the patient-based microenvironments. MCF7 cells growing in PDSs showed increased resistance to 4OHT and fulvestrant treatment (100- and 20-fold) compared to 2D cultures. Quantitative PCR analyses of endocrine treated cancer cells in PDSs revealed upregulation of pluripotency markers further supported by increased self-renewal capacity in sphere formation assays. When comparing different 3D growth platforms including PDS, matrigel, gelatin sponges and 3D-printed hydrogels, 3D based cultures showed slightly varying responses to fulvestrant and palbociclib whereas PDS and matrigel cultures showed more similar gene expression profiles for 4OHT treatment compared to the other platforms. The results support that the PDS technique maximized to provide a multitude of smaller functional PDS replicates from each primary breast cancer, is an up-scalable patient-derived drug-testing platform available for gene expression profiling and downstream functional assays.
Highlights
Three-dimensional cell culture platforms based on decellularised patient-based microenvironments provide in vivo-like growth conditions allowing cancer cells to interact with intact structures and components of the surrounding tissue
Primary breast cancer samples obtained from surgery were exposed to a series of detergent-washing steps generating cell-free patient-derived scaffolds (PDSs) that were re-cellularised with estrogen receptor-α (ERα)-positive MCF7 cells and cultured for 21 days (Fig. 1a)
To optimize and maximize the number of functional PDS replicates obtained from each piece of cancer tissue, we included a cryosectioning step before the re-cellularization
Summary
Three-dimensional cell culture platforms based on decellularised patient-based microenvironments provide in vivo-like growth conditions allowing cancer cells to interact with intact structures and components of the surrounding tissue. A patient-derived scaffold (PDS) model was evaluated as a testing platform for the endocrine therapies (Z)-4-Hydroxytamoxifen (4OHT) and fulvestrant as well as the CDK4/6-inhibitor palbociclib, monitoring the treatment responses in breast cancer cell lines MCF7 and T47D adapted to the patient-based microenvironments. There is a need for novel methods taken the influence of the cancer microenvironment on cellular responses into account when modelling cancer in vitro To address this issue, several scaffold-based techniques that can be used for largescale drug screening studies have emerged often using artificial biomaterials to create a surrogate scaffold for the cancer cells. We have described the refinement of the PDS model to suit anti-cancer drug validations and further analyzed the effect of endocrine therapies and the CDK4/6-inhibitor palbociclib in PDS cultures using ERα-positive cancer cell lines. The PDS system was compared to other commonly used 3D culture techniques and, unique properties of the PDS system was defined facilitating the development of clinically relevant approaches for anti-cancer drug development
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