Deletion of FAT1 in hybrid EMT cells stimulates the migration of neighboring non-mutant cells through secretion of extracellular vesicles

Cells in hybrid state of the epithelial-to-mesenchymal transition (EMT) have been shown to be responsible for tumor cell metastasis. However, the precise mechanisms underlying the morphological changes and acquisition of invasive phenotypes in hybrid EMT cells are still unknown. Here, we introduced the deletion of a proto-cadherin and well described oncogene, FAT1, in skin carcinoma cells to generate a hybrid state of EMT. Surprisingly, the FAT1 knock-out (KO) cells were less motile than the parental non-mutated cell line they were derived from. However, we observed that FAT1 KO cells secrete specific factors in the form of extra-cellular vesicles into their microenvironment, which promote the migration of surrounding non-mutant cells. When stimulated with these extracellular vesicles, groups of non-mutated parental cells collectively migrated faster and formed finger-like instabilities at the migrating front. Furthermore, we found that the actomyosin contractility of FAT1 KO cells in hybrid EMT states was much lower than the parental cells. It appeared that the factors secreted by FAT1 KO cells relaxed the traction forces in recipient cells. This force release likely fostered the scattering and migration of non-mutated cells surrounding FAT1 mutant cells. Thus, we characterized a non-autonomous promotion of cell invasiveness in the cancer cells surrounding FAT1-deficient cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/556588v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@104063eorg.highwire.dtl.DTLVardef@135f9fforg.highwire.dtl.DTLVardef@b0052eorg.highwire.dtl.DTLVardef@243864_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure:C_FLOATNO Schematic showing how FAT1 deletion stimulates the migration of neighboring non mutant cells. FAT1 KO cells secrete extracellular vesicles that carry factors that promote migration of non-mutant control cells, possibly through relaxation of traction forces in the recipient cells. C_FIG