During migration through tissues, metastatic cancer cells experience varying degrees of physical confinement. We hypothesized that cell volume regulation is especially important for migration in confined microenvironments. In combination with live cell imaging, we used a microfluidic-based chemotactic device with narrow extracellular matrix-coated channels to maintain distinct extracellular osmolarities at the leading and trailing edges of the cell. Upon switching from isotonic to hypotonic medium at the top of the chamber, we observed a rapid reversal of cell migration direction. A similar response was observed in multiple cancer cell lines (AB3 mouse sarcoma, HTB-94 human sarcoma, and MDA-MB-231 breast cancer), though the threshold osmolarity necessary to produce a response varied between cell types. Changes in cell migration velocity were accompanied by a decrease in volume, the kinetics and final value of which were dependent on the polarity of the osmotic shock (top, bottom, or top and bottom of the chamber), osmolarity, and cell type. Importantly, inhibition of actin polymerization, but not myosin II, stalled cell reversal after switching medium to hypotonic at the top of the chamber, even though actin-inhibited cells migrated normally during confined migration in isotonic medium. We also observed that microtubule dynamics are drive cell polarity changes, and we expect that ion channels and aquaporins will regulate cell volume changes that occur in these confined spaces upon osmotic shock. To further explain our results, we are also developing a theoretical model that relies on flux of ions and fluid flow into and out of the cell. Together,our results indicate that cancer cell migration in confined microenvironments is sensitive to fluctuations in extracellular osmolarity, and the location of osmotic shock (leading vs. trailing edge of the cell) is critical in directing the cellular response.

Osmotic regulation of cell migration and volume in confined microenvironments

245th National Meeting (2013)

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