Cancer cell-macrophage fusion increases tumor cell heterogeneity and reshapes their microenvironment

The trademark of cancer is the ability to evolve, which lays the grounds for progressive events such as metastasis and recurrence. Although genetic mutations and epigenetic changes have been implicated as the mechanisms, they don’t explain why many cancers develop leukocytic traits. Cell fusion between cancer and somatic cells, particularly macrophages, has been suggested as an alternative pathway for cancer cells to obtain new traits via acquiring exogenous genetic material. In this study, tumor-macrophage hybrid cells were generated, and two clones, both grew slowly yet with very different tumorigenicity, were selected for further study. Despite their very different abilities to form tumors in mice, both clones showed significant abilities to influence the tumor microenvironment. RNA-seq of the hybrid cell clones revealed the differential expression profiles of the hybrid cells that contributed to the biological behaviors. This study emphasizes the role of hybrid cells as potent environmental modifiers that aid tumor survival and evolution despite their minority status among the tumor cells. This study also provides an animal experimental platform to study cancer-myeloid fusion and a potential direction for novel therapeutic interventions.