Chromosomal instability (CIN), an elevated rate of chromosomal errors, leads to aneuploid cells and is associated with cancer. How CIN is initiated at the molecular level, and whether modest upregulation of certain cancer genes can trigger the onset of CIN, is poorly understood. To answer these questions, Elina Vladimirou and colleagues (Dale, Armond et al., 2022) use CRISPR activation to individually upregulate 14 different genes known to be important in cancer, combined with high-throughput confocal imaging of cells and an image analysis pipeline to detect CIN initiation by automated counting of centromeres and micronuclei. They show that the biggest shifts in centromere counts occur upon upregulation of CCND1, FOXA1 and NEK2, while upregulation of expression of the plus-end-directed motor protein KIF11 increases the incidence of micronuclei. The authors then focus on KIF11 to understand the mechanistic links between its activation and the CIN phenotype; they reveal that a fourfold increase in KIF11 causes fragmentation of the pericentriolar material, increased microtubule stability, mitotic catastrophe and lagging chromosomes, ultimately leading to chromosome segregation failures. Together, these findings demonstrate that relatively moderate upregulation of certain genes, such as KIF11, is sufficient to initiate CIN by exposing fragilities in the mitotic spindle, which has important implications for understanding cancer initiation.
