Development of bioengineered 3D patient derived breast cancer organoid model focusing dynamic fibroblast-stem cell reciprocity.

Abstract

Three-dimensional (3D) models, such as tumor spheroids and organoids, are increasingly developed by integrating tissue engineering, regenerative medicine, and personalized therapy strategies. These advanced 3Din-vitromodels are not merely endpoint-driven but also offer the flexibility to be customized or modulated according to specific disease parameters. Unlike traditional 2D monolayer cultures, which inadequately capture the complexities of solid tumors, 3D co-culture systems provide a more accurate representation of the tumor microenvironment. This includes critical interactions with mesenchymal stem/stromal cells (MSCs) and induced pluripotent stem cells (iPSCs), which significantly modulate cancer cell behavior and therapeutic responses. Most of the findings from the co-culture of Michigan Cancer Foundation-7 breast cancer cells and MSC showed the formation of monolayers. Although changes in the plasticity of MSCs and iPSCs caused by other cells and extracellular matrix (ECM) have been extensively researched, the effect of MSCs on cancer stem cell (CSC) aggressiveness is still controversial and contradictory among different research communities. Some researchers have argued that CSCs proliferate more, while others have proposed that cancer spread occurs through dormancy. This highlights the need for further investigation into how these interactions shape cancer aggressiveness. The objective of this review is to explore changes in cancer cell behavior within a 3D microenvironment enriched with MSCs, iPSCs, and ECM components. By describing various MSC and iPSC-derived 3D breast cancer models that replicate tumor biology, we aim to elucidate potential therapeutic targets for breast cancer. A particular focus of this review is the Transwell system, which facilitates understanding how MSCs and iPSCs affect critical processes such as migration, invasion, and angiogenesis. The gradient formed between the two chambers is based on diffusion, as seen in the human body. Once optimized, this Transwell model can serve as a high-throughput screening platform for evaluating various anticancer agents. In the future, primary cell-based and patient-derived 3D organoid models hold promise for advancing personalized medicine and accelerating drug development processes.