| Most solid tumors are aneuploid and frequently mis-segregate chromosomes during cell division. This chromosomal instability frequently arises from persistent mal-oriented attachments of chromosomes to spindle microtubules at kinetochores. The defects in cancer cells that prevent the correction of these attachment errors have not been identified and the process by which normal cells are capable of correcting attachment errors and faithfully segregating their chromosomes is poorly understood. Moreover, the specific contribution of chromosome mis-segregation, that results from these mal-attachments, to tumorigenesis is unknown. Here, four proteins were identified (Kif2b, MCAK, Astrin, and Kif18a) that influence kinetochore-microtubule dynamics during different phases of mitosis. By depleting these proteins in single and in combination, I define the dynamic range of kinetochore-microtubule attachment that leads to timely satisfaction of the spindle assembly checkpoint while allowing for sufficient kinetochore-microtubule release rates to correct attachment errors and support faithful chromosome segregation. Intriguingly, kinetochore-microtubule stability in chromosomally unstable cancer cells exceeds the threshold necessary for efficient correction of mal-oriented attachments. Furthermore, targeted disruption of a tumor suppressor gene (APC) hyperstabilizes kinetochore-microtubules in diploid cells and induces chromosome segregation errors consistent with its loss-of-function phenotype in tumors. On the other hand, overexpression of either Kif2b or MCAK, leads to increased kinetochore-microtubule dynamics, reduction in chromosome mis-segregation rates and suppression of chromosomal instability. This finding was used to directly test the contribution of chromosome mis-segregation toward tumor growth by overexpressing Kif2b in a glioblastoma cell line. Xeno-transplantation of these cells into immuno-compromised mice reveals that promoting kinetochore-microtubule dynamics leads to accelerated tumor growth rates. Thus, chromosomal instability, and not aneuploidy per se, limits tumor growth and frequently arises when kinetochore-microtubule dynamics in cancer cells deviate from a narrow, temporally-defined, and permissible range required for accurate chromosome segregation. |
