Abstract
Cell-cell fusion describes the process by which two cells combine their plasma membranes and become a single cell, possessing and retaining 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. The resulting hybrid cells were aneuploid and possessed enhanced clonal diversity and chemoresistance compared to non-hybrid cancer cells. We also observed cell-cell fusion to occur in vivo between melanoma cells and non-cancer cells of both hematopoietic and non-hematopoietic lineages. These findings suggest that cell-cell fusion occurs during the natural progression of cancer 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.
Highlights
Cell-cell fusion refers to the process by which two or more cells combine their plasma membranes to become a single hybrid cell containing DNA from each parent cell [1]
As an initial proof-of-concept that Cre transfer occurs between cancer and non-cancer cells, we cocultured mouse embryonic fibroblasts (MEFs) derived from reporter mice (B6.Cg-Gt(ROSA)26Sortm9(CAGtdTomato)Hze/J) with B16.F10 melanoma cells expressing GFP-Cre (B16-GFP-Cre) for 24 and 48 hours and measured tdTomato fluorescence by FACS
B16-derived Cre was transferred to other cell types derived from reporter mice, including adult dermal fibroblasts (ADF), bone marrow-derived macrophages (BMDM), and peritoneal macrophages, albeit with differing levels of efficiency (0.5–5%) (Figure 1C)
Summary
Cell-cell fusion refers to the process by which two or more cells combine their plasma membranes to become a single hybrid cell containing DNA from each parent cell [1]. In the context of cancer, it has been hypothesized that cell-cell fusion may act to increase the genotypic and phenotypic diversity of daughter cells [8] This mechanism of DNA exchange, via “sexual reproduction” (fusion and subsequent reductive division), is thought to be a more efficient way to generate populational heterogeneity as opposed to relying on the accumulation of oncogenic mutations in a single cell (“asexual reproduction”). Based on this hypothesis, hybrid cells are more likely to possess characteristics that would allow for the progressive growth of cancer compared to non-hybrid cells. While definitive evidence linking cell fusion to cancer progression in humans is lacking, it has become increasingly clear using animal models that cell fusion plays a physiologically relevant role in the progression of cancer [18], especially as it relates to metastasis [19, 20], drug resistance [21], and cancer stem cell formation [9, 10]
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