Metastasis: Slipping Control

‘‘And now here it was again, now grown, now in its new home.’’ In her book Resilience, Elizabeth Edwards recalls what raced through her mind when she learned that her cancer had come back and had metastasized. After surgery, radiation, and chemotherapy, she thought that the cancer ‘‘had been chased away.’’ How does cancer find a new home and become metastatic? The short answer is simple: it is complicated. As cancer forms and develops, some cancer cells manage to be disseminated from the primary tumor, travel through the circulatory system, and infiltrate and colonize distant organs, eventually forming clinically detectable metastasis. Given the complexity of the metastatic process and technical and experimental bottlenecks, systematically investigating metastasis has been challenging, and to this date, metastatic cancer also remains largely incurable and fatal. Nevertheless, with the availability of more pathophysiologically relevant disease models and technological advances in areas such as imaging and single-cell sequencing, recent studies are beginning to paint a clearer picture. Why does cancer come back as metastatic in some patients after the primary tumor has been successfully removed? The answer might have to do with the timing of metastatic dissemination. Earlier data from several tumor types already suggest that, contrary to more conventional thinking, dissemination can occur rather early during cancer development, but the mechanism of early dissemination is unknown. A pair of studies now offers important clues as to how this happens in breast cancer (Hosseini et al., 2016; Harper et al., 2016). Using a Her2-driven breast cancer mouse model, Housseini et al. and Harper et al. provide evi-