Synergistic inter-clonal cooperation involving crosstalk, co-option and co-dependency can enhance the invasiveness of genetically distant cancer clones.

Based on our findings, we propose a model in which crosstalk, co-option, and co-dependency can facilitate the evolution of synergistic cooperative interactions between genetically distant clones. Specifically, we suggest that synergistic cooperative interactions can easily emerge, regardless of the degree of overall genetic/genealogical relatedness, via crosstalk involving metastatic clones able to constitutively secrete molecules that induce and maintain their own malignant state (producer-responder clones) and clones that have the ability to respond to those signals (responder clones) and express a synergistic metastatic behaviour. Taking into account the lack of therapies that directly affect the metastatic process, interfering with such cooperative interactions during the early steps in the metastatic cascade could provide additional strategies to increase patient survival.