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

Initiation and progression of cancers reflect 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. 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. 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 asked 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 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 modeling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumor 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 tumor’s ability to adapt to new selective pressures. Affymetrix SNP arrays were performed according to the manufacturer's protocol. DNA was extracted from frosen cell pellet using Quiagen DNAeasy kit. 12 samples were analysed: 3 subclones of hybrid between Hs578T and MDA231 cell lines, 2 subclones of hybrid between MCFDCIS and SUM159 cell lines. Parental cell lines, 2 replicates of each, except for MCFDCIS: Hs578T, MDA231, SUM159, MCFDCIS. Cell were grown in correcponding media before collecting the samples, no treatment was applied.