SUMMARY Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways exist that limit the prevalence of such cells? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance.

The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, the majority of mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs due to chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future anti-mitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.

Significance Aneuploidy, an abnormal chromosome content that commonly occurs because of errors in chromosome segregation, can promote or suppress tumor formation. What determines how aneuploidy influences tumorigenesis has remained unclear. Here we show that the rate of chromosome missegregation, rather than the level of accumulated aneuploidy, determines the effect on tumors. Increasing the rate of chromosome missegregation beyond a certain threshold suppresses tumors by causing cell death. Increasing errors of chromosome segregation did not affect tumor formation caused by genetic mutations that do not themselves alter chromosome inheritance. These results suggest that accelerating chromosome missegregation in chromosomally unstable tumors may be a useful strategy therapeutically.

Summary Errors in chromosome segregation during mitosis have been recognized as a hallmark of tumor cells since the late 1800s, resulting in the long-standing hypothesis that mitotic abnormalities drive tumorigenesis. Recent work has shown that mitotic defects can promote tumors, suppress them, or do neither, depending on the rate of chromosome missegregation. Here we discuss the causes of chromosome missegregation, their effects on tumor initiation and progression, and the evidence that increasing the rate of chromosome missegregation may be an effective chemotherapeutic strategy.