A mechanism linking extra centrosomes to chromosomal instability

Abstract

The mechanism underlying chromosomal instability (CIN), an increased rate of gain or loss of whole chromosomes that is common in cancer cells, has been the subject of much debate. Long-term live-cell imaging now reveals that extra-centrosomal cancer cells pass through a transitory multipolar spindle stage, when abnormal kinetochore-microtubule attachments accumulate. Many attachment errors persist even after the extra centrosomes cluster to form proper bipolar spindles, increasing the likelihood of chromosome missegregation. The cover shows a transient multipolar spindle intermediate in a human cell with extra centrosomes. Microtubules are shown red, centrosomes green and chromosomes white. Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes, but a direct mechanistic link between CIN and extra centrosomes has not been established. Live-cell imaging is now used to demonstrate that extra centrosomes can promote chromosome missegregation as a consequence of cells passing through a transient 'multipolar spindle intermediate'. Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes1,2,3,4. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient ‘multipolar spindle intermediate’ in which merotelic kinetochore–microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer.