ABSTRACTInitiation and progression of cancers is underpinned by somatic evolution, which follows 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 to lack access to (para)sexual recombination - one of the most powerful diversification mechanisms throughout all strata of life. Based on

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... ions of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in yeast, we set to interrogate 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 ploidy reduction, generating diverse progeny with heterogeneous combinations of genetic and phenotypic traits of fusion parents. 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 adaptive landscapes relative to strictly asexual populations, which may substantially accelerate tumor evolution.