T117

During cancer development, tumor cells gain the ability to invade and metastasize. Individual cells use alternative migration modes based on different cellular mechanisms. One of them is mesenchymal motility mode which is driven by leading edge protrusion in the form of filopodia or/and lamellipodia based on Arp2/3 dependent actin polymerization. Mesenchymal motility depends on formation of cell-substrate adhesions, activity of matrix metalloproteases (MMPs) and on activity of small GTPaseRac. Another mode is amoeboid motility, which involves formation of blebs – hollow membrane protrusions extruded from the cell surface by actin-myosin contraction. Amoeboid motility does not need both pronounced cell-substrate adhesions and MMPs activity and required increase of activity of small GTPase Rho. Fibroblasts and scattered epithelial cells migrate by mesenchymal mode, while blood cells – lymphocytes or macrophages mainly use amoeboid mode for migration. It was shown that some treatments cause transition from one motility mode to another. Switches from mesenchymal to amoeboid motility and opposite are called mesenchymal-amoeboid transition (MAT) and amoeboid -mesenchymal transition (AMT) respectively. The ability of cells for such transitions was named as plasticity of migration. We compared the plasticity of migration of normal and tumor cells. To study plasticity of mesenchymally migrated cells (MAT) we choose fibrosarcoma cells HT1080 as tumor and non-transformed subcutaneous fibroblasts 1036 as normal counterpart. To study AMT we choose a few lines of myeloid leukemia THP1, K562, KG1 in contrast to normal leukocytes obtained from healthy donors. We showed that fibrosarcoma cells in opposite to non-transformed fibroblasts could undergo MAT under treatments, which limited mesenchymal migration. Two approaches to limit mesenchymal motility of cells were used. One was decrease of substrate adhesiveness by treatment of coverslips with PolyHema solutions, which simulated the alteration of environmental conditions during cell migration. The other approach was influence on cellular pathways regulated cell motility. We used CK666, the inhibitor of Arp2/3 activity, which stopped actin polymerization and thus lamellipodia formation through Arp2/3 dependent mechanism. We showed that under both treatments the fraction of tumor cells switched from lamellipodia formation to blebbing and thus underwent MAT, while in non-transformed fibroblasts these treatments led to retraction of lamellipodia and significant failure of motility. Both leukemia cells and leucocytes of healthy donors showed blebs formation (amoeboid motility). We induced transition to mesenchymal motility by alteration of culture conditions. The first approach was the increase of substrate adhesiveness by treatment with fibronectin. Another way was to inhibit of small GTPase Rho activity. In result of both treatments, leukemia cells switched from amoeboid to mesenchymal motility (underwent AMT), but leucocytes of healthy donor could not do such transition. For the first time it was shown that AMT is features of leukemia cells but not leucocytes from healthy donors. Both MAT and AMT are reversible, meaning that cells exhibiting plasticity could change motility mode in dependence on environment. Our results demonstrate that tumor cells of different origin could transit from one mode of motility to another and normal cells could not undergo such transitions. We also investigate the effectiveness of amoeboid and mesenchymal motility during migration in different environments. It was shown that the mesenchymal motility is more effective for 2D migration, while the amoeboid motility is more effective in 3D conditions. During dissemination, cells go beyond the borders of original tissues and pass through environment with different properties. The plasticity of migration triggered by alteration of entire or internal conditions dramatically increases ability of cells to disseminate. The ability of tumor cells to plasticity permits them to choose optimal mode for migration, thus leading to metastasis development.