Abstract C65: Mechanisms to maintain extra centrosomes in cancer cells

Abstract

Abstract Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. Using a genome-wide RNAi screen in Drosophila S2 cells, we defined several mechanisms that suppress multipolar mitoses. We also found that HSET, a normally non-essential kinesin motor was essential for the viability of cancer cells containing extra centrosomes. Interestingly, using fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. Thus, cell adhesion is an important morphological feature that contributes to centrosome clustering. Importantly, during tumor progression, changes in cell architecture and adhesion patterns, such as loss of E-cadherin and acquisition of an elongated cell shape, are often observed. This is referred to as the epithelial-to-mesenchymal transition (EMT). The presence of extra centrosomes is often correlated with more malignant tumors, which lost their epithelial phenotype most likely through EMT. Thus, we hypothesized that the ability of cells to cluster extra centrosomes varies between epithelial cells and non-epithelial cells. To test this idea we used a panel of non-transformed mammalian epithelial and non-epithelial cell lines and quantified their ability to cluster extra centrosomes. We treated cells with DCB to generate tetraploid cells containing extra centrosomes and followed them by live-cell imaging. We found that non-epithelial cells cluster their extra centrosomes much more efficiently than epithelial cells. This finding suggests that loss of cell-cell adhesion might facilitate centrosome clustering. Consistent with this idea, our preliminary data indicate that induction of EMT in the epithelial cell lines MCF10A and MDCK increases the number of tetraploid cells that undergo a bipolar mitosis. We propose that changes that take place during tumor progression, such as loss of cell-cell adhesion, might facilitate centrosome clustering and therefore increase the ability of cancer cells to maintain extra centrosomes. We are currently investigating the nature of the changes that occur during EMT that facilitate centrosome clustering. Citation Information: Cancer Res 2009;69(23 Suppl):C65.