Spontaneous cell fusions as a mechanism of parasexual recombination in tumour cell populations

Abstract

The initiation and progression of cancers reflect the underlying process of somatic evolution, in which the diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination-a key diversification mechanism throughout all strata of life. On the basis of observations of spontaneous fusions involving cancer cells, the reported genetic instability of polypoid cells and the precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions between genetically distinct cancer cells could produce parasexual recombination. Using differentially labelled tumour cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo. While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. 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 modelling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumour cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape (relative to strictly asexual populations), which may substantially accelerate a tumour's ability to adapt to new selective pressures.