Decoding physical principles of cell migration under controlled environment using microfluidics.

Living cells can perform incredible tasks that man-made micro/nano-sized robots have not yet been able to accomplish. One example is that white blood cells can sense and move to the site of pathogen attack within minutes. The robustness and precision of cellular functions have been perfected through billions of years of evolution. In this context, we ask the question whether cells follow a set of physical principles to sense, adapt, and migrate. Microfluidics has emerged as an enabling technology for recreating well-defined cellular environment for cell migration studies, and its ability to follow single cell dynamics allows for the results to be amenable for theoretical modeling. In this review, we focus on the development of microfluidic platforms for recreating cellular biophysical (e.g., mechanical stress) and biochemical (e.g., nutrients and cytokines) environments for cell migration studies in 3D. We summarize the basic principles that cells (including bacteria, algal, and mammalian cells) use to respond to chemical gradients learned from microfluidic systems. We also discuss about novel biological insights gained from studies of cell migration under biophysical cues and the need for further quantitative studies of cell function under well-controlled biophysical environments in the future.

Mechanical compression regulates tumor spheroid invasion into a 3D collagen matrix.

Uncontrolled growth of tumor cells in confined spaces leads to the accumulation of compressive stress within the tumor. Although the effects of tension within 3D extracellular matrices (ECMs) on tumor growth and invasion are well established, the role of compression in tumor mechanics and invasion is largely unexplored. In this study, we modified a Transwell assay such that it provides constant compressive loads to spheroids embedded within a collagen matrix. We used microscopic imaging to follow the single cell dynamics of the cells within the spheroids, as well as invasion into the 3D ECMs. Our experimental results showed that malignant breast tumor (MDA-MB-231) and non-tumorigenic epithelial (MCF10A) spheroids responded differently to a constant compression. Cells within the malignant spheroids became more motile within the spheroids and invaded more into the ECM under compression; whereas cells within non-tumorigenic MCF10A spheroids became less motile within the spheroids and did not display apparent detachment from the spheroids under compression. These findings suggest that compression may play differential roles in healthy and pathogenic epithelial tissues and highlight the importance of tumor mechanics and invasion.

Mechanical compression regulates tumor spheroid invasion into a 3D collagen matrix.

Uncontrolled growth of tumor cells in confined spaces leads to the accumulation of compressive stress within the tumor. Although the effects of tension within 3D extracellular matrices on tumor growth and invasion are well established, the role of compression in tumor mechanics and invasion is largely unexplored. In this study, we modified a Transwell assay such that it provides constant compressive loads to spheroids embedded within a collagen matrix. We used microscopic imaging to follow the single cell dynamics of the cells within the spheroids, as well as invasion into the 3D extracellular matrices (EMCs). Our experimental results showed that malignant breast tumor (MDA-MB-231) and non-tumorigenic epithelial (MCF10A) spheroids responded differently to a constant compression. Cells within the malignant spheroids became more motile within the spheroids and invaded more into the ECM under compression; whereas cells within non-tumorigenic MCF10A spheroids became less motile within the spheroids and did not display apparent detachment from the spheroids under compression. These findings suggest that compression may play differential roles in healthy and pathogenic epithelial tissues and highlights the importance of tumor mechanics and invasion.

Tumor spheroid invasion in epidermal growth factor gradients revealed by a 3D microfluidic device.

Epidermal growth factor (EGF), a potent cytokine, is known to promote tumor invasion bothin vivoandin vitro. Previously, we observed that single breast tumor cells (MDA-MB-231 cell line) embedded within a 3D collagen matrix displayed enhanced motility but no discernible chemotaxis in the presence of linear EGF gradients using a microfluidic platform. Inspired by a recent theoretical development that clustered mammalian cells respond differently to chemical gradients than single cells, we studied tumor spheroid invasion within a 3D extracellular matrix (ECM) in the presence of EGF gradients. We found that EGF gradients promoted tumor cell detachment from the spheroid core, and the position of the tumor spheroid core showed a mild chemotactic response towards the EGF gradients. For those tumor cells detached from the spheroids, they showed an enhanced motility response in contrast to previous experimental results using single cells embedded within an ECM. No discernible chemotactic response towards the EGF gradients was found for the cells outside the spheroid core. This work demonstrates that a cluster of tumor cells responds differently than single tumor cells towards EGF gradients and highlights the importance of a tumor spheroid platform for tumor invasion studies.