Our laboratory aims to understand normal cell division mechanisms and to discover cell division defects that are unique to cancer cells. We take a range of approaches including genetics, functional genomics, biochemistry and live cell imaging. There are ongoing projects using yeast, tissue culture cells, and genetically engineered mice.
Our work on cytoskeletal dynamics is focused on the mechanism of chromosome segregation in normal cells and cancer cells. We have a long-standing interest in spindle orientation, centrosome position, and asymmetric cell division. We discovered mechanisms that link microtubules to polarized actin in yeast, and have recently defined analogous mechanisms in human cells. We study how centrosome amplification in cancer cells impacts cellular adhesion, cell migration, and tumor invasion. We have discovered new drug targets that kill cancer cells because of their centrosome amplification. We use biochemical and imaging approaches to understand these processes at a mechanistic level.
We are also interested in how aneuploidy (abnormal chomosome number) impacts tumor biology. We are particularly interested in the consequences of whole genome duplications, which recent genomic data suggest occur in nearly 40% of human cancers. We previously found that whole genome duplications resulting from cytokinesis failure can drive tumor development. We recently identified a mechanism by which errors in the segregation of intact chromosomes can cause DNA breaks, potentially resulting in cancer-causing mutations. These findings may explain the recently discovered phenomenon of chromothripsis, where a single chromosome or chromosome arm appears to undergo massive breakage and rearrangement. We are using single cell genome sequencing to define the impact of cell division errors on genome architecture.
Our work on cytoskeletal dynamics is focused on the mechanism of chromosome segregation in normal cells and cancer cells. We are particularly interested in how the microtubule and actin cytoskeletons interact. For example, we have recently uncovered a mechanism by which actin organization and the adhesive microenvironment of cells influence chromosome segregation. We have defined cytoskeletal mechanisms that control polarized cell growth and asymmetric cell division. We use biochemical and imaging approaches to understand these processes at a mechanistic level as well as to understand how these events are properly timed during the cell cycle.
In Fujiwara et al.,
10 of 39 injections of tetraploid-derived mouse mammary epithelial cells (MMECs) produced mammary tumors within 12 weeks of injection, while 0 of 41 injections of isogenic diploid-derived control cells did. Click to enlarge
We are also interested in how aneuploidy (abnormal chomosome number) and polyoidy (increased sets of chromosomes) impact on tumor biology. We recently found that failure of cytokinesis, which doubles the number of chromosomes and centrosomes, promotes tumorigenesis in a mouse breast cancer model. We are studying the consequences of having extra centrosomes in cancer cells. Finally, we are taking various approaches to understand the consequences of having extra chromosomes (aneuploidy) in cells. For example, we are using yeast to ask whether aneuploidy or polyploidy can affect the rate of adaptation (evolution).