Eighty five percent of cancer related deaths are due to solid tumors, and the majority of these deaths are caused by the formation of metastases. Metastasis
formation is a complex, multistage process involving modulation of cell phenotype, cell migration, and dynamic homotypic and heterotypic cell-cell
interactions. Following the epithelial to mesenchymal transition, cells migrate away from the primary tumor mass, and an ensemble of mechanical and chemical
signals guide their migration. Migrating tumor cells respond to ECM stiffness gradients and fiber alignment, soluble chemical factors from neighboring and
distant cells, and chemicals that bind to or release from the ECM. The numerous migratory stimuli act in parallel and compete to guide the direction,
velocity, and persistence of cell migration.
Because single cell migration precedes the formation of metastatic lesions, understanding the mechanisms by which migrating tumor cells sense and respond to
environmental signals is crucial for cancer treatment and metastasis prevention. Systematically evaluating the relative importance of a single stimulus or a
subset of stimuli requires a reductionist platform in which the tumor cell environment can be predictably and repeatedly engineered.
We developed a microfluidic system in which we can modulate the chemical and mechanical microenvironment of tumor cells, and we have used this system to
investigate the role of fluid flow on cell migration. We found that chemical stimuli, resulting from the redistribution of soluble ligand in a flow field,
compete with mechanical stimuli, resulting from fluid shear and pressure stresses on the cell, to guide cell migration. We are now using fluorescent
biosensors to understand the molecular mechanisms behind the fluid stress mediated response, and recently we have implemented a new microfluidic platform
to guide the migration of tumor cells using soluble growth factor gradients. Data from the microfluidic devices are informing the development of a
computational model for cell migration, which we will implement to simulate the response of tumor cells to physiologic stimuli.
Microfluidic device for investigating effect of fluid flow on tumor cell migration. Cells were seeded in a collagen hydrogel polymerized between PDMS posts (white rectangles above), and a fluid pressure gradient across the hydrogel drives fluid flow through the gel.