FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer

Tumour heterogeneity is a major factor undermining the success of therapies targeting metastatic cancer. Two major theories are thought to explain the phenomenon of heterogeneity in cancer--clonal evolution and cell plasticity. In this review, we examine a growing body of work implicating the transcription factor FOS-related antigen 1 (FRA-1) as a central node in tumour cell plasticity networks, and discuss mechanisms regulating its activity in cancer cells. We also discuss evidence from the FRA-1 perspective supporting the notion that clonal selection and cell plasticity represent two sides of the same coin. We propose that FRA-1-overexpressing clones featuring high plasticity undergo positive selection during consecutive stages of multistep tumour progression. This model underscores a potential mechanism through which tumour cells retaining elevated levels of plasticity acquire a selective advantage over other clonal populations within a tumour.