Initiation and progression of cancers reflects the underlying process of somatic evolution, which follows a Darwinian logic, i.e. , diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Whereas somatic evolution can tap into multiple sources of diversification, it is assumed that it lacks access to (para)sexual recombination—one of the most powerful diversification mechanisms throughout all strata of life. Based on observations of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in fungi, we interrogated whether cell fusions could serve as a source of parasexual recombination in cancer cell populations. Using differentially labelled tumor cells, we found evidence of low-frequency, spontaneous cell fusions in all of the tested breast cancer cell lines both in vitro and in vivo . While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous combinations of parental alleles. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modeling, we demonstrated that observed rates of spontaneous somatic cell fusions may allow populations of tumor cells to explore larger areas of the adaptive landscape, relative to strictly asexual populations, which may substantially accelerate a tumor’s ability to adapt to new selective pressures.

Spontaneous Cell Fusions as a Mechanism of Parasexual Recombination in Tumor Cell Populations