“Centrosomes: from C. elegans to a potential cancer therapeutic”

Functional genomic and proteomic approaches in models such as the early C. elegans embryo helped uncover conserved molecular machinery involved in cell division.  In my talk, I will focus on centrosomes, the major microtubule-organizing centers of animal cells that promote spindle formation during cell division.  Functional genomic screens in C. elegans identified the components involved in centrosome duplication and in their function as scaffolds for microtubule generation.  Following the initial discovery and characterization phase, we initiated a collaborative effort to target the key regulator of centrosome assembly – the kinase Plk4 – using small molecule inhibitors in human cells.  This effort culminated in the development of centrinone, a potent, specific and cellularly active Plk4 inhibitor which enables routine generation of centrosome-less human cells. Using centrinone, we have identified specific cancer contexts where cell division is highly sensitive to centrosome loss.  I will discuss our efforts to understand the reasons for this sensitivity, which is revealing new mechanisms acting during cell division and is helping identify contexts where Plk4 inhibition may provide a therapeutic benefit.