Fluidic substrate as a tool to probe breast cancer cell adaptive behavior in response to fluidity level

Abstract

Although the roles of elastic components in breast cancer progression have been widely studied, the importance of matrix dissipative elements in regulating breast cancer behavior is still poorly understood. In this study, we designed viscosity-tunable fluidic substrates to investigate the effects of matrix viscosity on the alteration of breast cancer cellular fate using a hydrophobic molten polymer of poly(e-caprolactone-co-D,L-lactide) [P(CL-co-DLLA)] with different levels of fluidity. The high- and low-fluidity substrates used in this study were shown to behave as viscoelastic liquids at physiological temperature. A nonmetastatic breast cancer cell line (MCF-7) was cultured at the interface of the fibronectin-coated substrate, and its behavior towards the substrate fluidity level was thoroughly characterized. Despite fibronectin-mediated cell-substrate interactions, MCF-7 cells show sensitivity to substrate fluidity levels by forming types aggregates of different sizes and structures over time. Accordingly, MCF-7 cells were undergoing senescence on fluidic substrates, as shown by high metabolic activity over time, suppressed proliferation ability, and positive expression of senescence markers. Moreover, senescence implies more resistance towards anticancer drug treatment. This indicates that a fluidic substrate, as a two-dimensional synthetic matrix system, could demonstrate the importance of mechanical cues in redefining cellular function and cellular fate by changing the viscosity of the pure substrate. A fluidic substrate behaving as a hydrophobic viscoelastic liquid was designed as a tool to investigate the role of matrix viscosity on the alteration of breast cancer cellular fate. The fluidity level of fluidic substrate was tuned by modulating the molecular weight of poly(e-caprolactone-co-D,L-lactide). MCF-7 cells responded to the change in fluidity level of fluidic substrates by forming weak attachment. On high-fluidity substrate, MCF-7 cells formed 3D aggregates, while coalesced on low-fluidity substrate. More importantly, the fluidic substrate mechanically promoted senescence of MCF-7 cells regardless the fluidity level of substrate.