William Saunders

The research of the Saunders lab is focused on the study of cell division and the origin of divisional defects in cancer cells. When cells divide, it is essential that the components of the cell are separated such that both daughters will inherit the necessary starting material to propagate as healthy cells. During tumorigenesis, cells often divide irregularly with missegregation of chromosomes and microtubule organizing centers or centrosomes. Both of these changes are thought to contribute to the enhanced mutational rates contributing to tumor progression.  Our interests are to define pathways required for normal division and determine how these pathways are altered in human disease.
 
Currently, we are focused on three types of abnormal division in tumor cells. These are multipolar spindles, failed cytokinesis and anaphase bridges.
 

Multipolar spindles happen when the cell tries to divide the chromosomes into more than two groups. This is a result of amplification and unclustering of the centrosomes in the cell. Centrosomes organize the microtubules into a spindle to separate the chromosomes during mitosis. Extra centrosomes can form more than two microtubule foci resulting in abnormal separation of the chromosomes into three or more groups (Figure 1). In cancer cells, multipolarity is achieved by interference with the microtubule motor called cytoplasmic dynein. Dynein is not visible on cancer cell spindles and inhibition of dynein can greatly increase the multipolarity resulting from centrosomal amplification. In some tumor cells, dynein is inhibited by overexpression of another spindle motor called NuMA.
 
A related question is how the centrosomes get amplified in the first place. Recent work in the lab has shown that centrosomes are amplified by failure of cytokinesis, the divisional process that occurs to the cell at the end of mitosis. Cytokinesis was shown to fail in cancer cells due to underphosphorylation of the regulatory myosin light chain.  We believe this inhibition occurs in cancer cells by overexpression of the cell cycle regulatory kinase Aurora B that phosphorylates the myosin light chain kinase reducing its abundance, localization and biochemical activity.  Deficient myosin light chain phosphorylation causes the cleavage furrow to regress.
 
The third divisional defects of cancer cells we study is anaphase bridges. These structures are a result of dicentric chromosomes attaching to both centrosomes and result in a tug-of-war between two dividing cells for a single chromosome (Figure 2). Our current focus is in role of chromatin bridges in activating Aurora B to inhibit   myosin light chain kinase leading to failure of cytokinesis and centrosomal amplification.