Cell-cell fusion as a mechanism of DNA exchange in cancer

Abstract

Abstract Cell-cell fusion is a common biological phenomenon involved in both healthy and disease conditions. Fusion occurs when two or more cells combine their plasma membranes and become a single hybrid cell that retains certain genetic information from each parent cell. Here, using a Cre-loxP-based method initially developed to investigate extracellular vesicle targeting, we found that cancer cells spontaneously and rapidly deliver DNA to non-cancer cells in vitro via a cell-cell fusion event. We found that B16 melanoma cells and progressor and regressor fibrosarcomas were capable of spontaneously fusing with immune cells (macrophages) and non-immune cells (fibroblasts) in vitro, with varying degrees of efficiency. Further analysis of hybrid clones resulting from fusion between B16 melanoma cells and mouse embryonic fibroblasts showed that these cells were aneuploid and possessed enhanced clonal diversity and chemoresistance compared to non-hybrid melanoma cells. We also observed cell-cell fusion to occur in vivo between melanoma cells and non-cancer cells of both hematopoietic and non-hematopoietic origin. These findings suggest that cell-cell fusion occurs in murine cancer models and show that this mechanism has the potential to cause massive genomic alterations that are observed in cancer. Furthermore, these findings somewhat contradict recent publications suggesting that the Cre-loxP method measures only extracellular vesicle-mediated intercellular communication.