Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

Abstract

The in vivo tumor microenvironment is a complex niche that includes heterogeneous physical structures, unique biochemical gradients and multiple cell interactions. Its high-fidelity in vitro reconstruction is of fundamental importance to improve current understandings of cell behavior, efficacy predictions and drug safety. In this study, we have developed a high-throughput biochip with hundreds of composite extracellular matrix (ECM) microchambers to co-culture invasive breast cancer cells (MDA-MB-231-RFP) and normal breast epithelial cells (MCF-10A-GFP). The composite ECM is composed of type I collagen and Matrigel which provides a heterogeneous microenvironment that is similar to that of in vivo cell growth. Additionally, the growth factors and drug gradients that involve human epidermal growth factor (EGF), discoidin domain receptor 1 (DDR1) inhibitor 7rh and matrix metalloproteinase inhibitor batimastat allow for the mimicking of the complex in vivo biochemical microenvironment to investigate their effect on the spatial-temporal dynamics of cell growth. Our results demonstrate that the MDA-MB-231-RFP cells and MCF-10A-GFP cells exhibit different spatial proliferation behaviors under the combination of growth factors and drugs. Basing on the experimental data, we have also developed a cellular automata (CA) model that incorporated drug diffusion to describe the experimental phenomenon, as well as employed Shannon entropy (SE) to explore the effect of the drug diffusion coefficient on the spatial-temporal dynamics of cell growth. The results indicate that the uniform cell growth is related to the drug diffusion coefficient, which reveals that the pore size of the ECM plays a key role in the formation of complex biochemical gradients. Therefore, our integrated, biomimetic and high-throughput co-culture platforms, as well as the computational model can be used as an effective tool for investigating cancer pathogenesis and drug development.