Motor proteins in spindle assembly: targets for cancer therapy?

Proper chromosome segregation requires the formation of a bipolar mitotic spindle. Although bipolar spindle formation and chromosome segregation occur with very high fidelity in normal cells, spindle abnormalities and chromosome segregation defects are very common in cancer cells. The mitotic spindle is a highly dynamic array of microtubules that is organized through the combined action of microtubule-organizing centers, a variety of microtubule-associated proteins and microtubule-dependent motor proteins such as kinesin-5 and dynein. Currently we do not have a good understanding of the way the different motor proteins work together to form a bipolar spindle, and how they contribute to spindle defects in cancerous cells. Also, little is known about the spatio-temporal regulation of motor proteins, while it is clear that this is an important aspect of spindle formation. In this proposal we aim to address the role of motor proteins during bipolar spindle assembly. In particular, we will study the specific function of two kinesins for which we have recently identified a novel role in spindle assembly. Their primary role in spindle formation, as well as their possible contribution to resistance to novel kinesin-targeting drugs that are currently developed for anti-cancer treatment will be investigated. In addition, we will study the spatio-temporal regulation of motor proteins during spindle assembly, to understand how local cues can control spindle bipolarity. This will involve both an in-depth analysis of post-translational modifications of kinesins with a role in spindle assembly, as well as systematic genome-wide screens for regulators of motor function. With these studies we aim to further characterize the mechanisms that control spindle assembly during mitosis, and gain a better understanding of the spatio-temporal control of spindle formation. This can help us resolve the defects that underlie aberrant spindle formation in cancer cells and develop and improve spindle targeting drugs for use in cancer therapies.