(148b) Rupture of Cancer Cells Under Microcirculatory Conditions

Survival of circulating tumor cells (CTCs) in blood circulation is essential for cancer metastasis. However, fluid forces in microcirculation have been shown to cause cell rupture, lending to the notion that such mechanical trauma of CTCs is responsible for metastatic inefficiency. Literature evidence for tumor cell death due to mechanical damage remains ambiguous and moreover the physical mechanisms of cell rupture are poorly understood. Here, we develop a microfluidic capillary model of microcirculation that contains an array of flow bifurcations and investigate rupture of tumor cells. We find that when a cancer cell arrives at a narrow bifurcation, it is strongly deformed and stretched into the bifurcating branches, eventually causing a cytosol-filled membrane-bound vesicle to be pinched-off. To identify the essential features of the mechanism underlying the rupture process, we used a library of drugs that (i) either enhance or inhibit the polymerization of actin and microtubules (ii) inhibit myosin II and decrease cortical tension, and (iii) condense and decondense nuclear chromatin. Results from these studies show that the mechanical properties of the membrane and cytoskeletal filaments play an important role in regulating the time-scale for rupture of tumor cells, but not the nucleus. In addition, the vesicle size was not sensitive to any of the drug treatments indicating that the cytosol content determines the vesicle volume. We develop a model that is a result of balance between external fluid pressure and stresses internal to the cell, which captures the key experimental observations. Taken together, our results support a picture, where under mechanical stress, the cytosol flows through the elastic cytoskeleton and fills the membrane that is detached from the cortex, similar to cellular blebbing. Finally, we find that a very small fraction of the ruptured tumor cells undergo apoptosis, suggesting that CTCs can survive the impact of fluid forces in microcirculation and that mechanical trauma is not a significant cause for metastatic inefficiency.