Wednesday, April 24, 2024
4/24/2024
Unscheduled whole-genome doubling events (WGD) give rise to polyploid cells that are associated with human disease. Most significantly, WGD generates genetically unstable tetraploid cells that can fuel tumorigenesis. Recent computational analyses have revealed that nearly 40% of all solid tumors have undergone at least one WGD, often early in their development, demonstrating that such events play significant roles in both the initiation and/or progression of human malignancies. Gaining a comprehensive understanding of the mechanisms through which whole-genome doubled cells arise and promote tumorigenesis is therefore a critical, albeit largely unexplored area of cell biology. The goal of this proposal is to combine computational, cell biological, and animal model methodologies to test the overarching hypothesis that whole genome-doubled cells must acquire specific genetic adaptations that enable them to tolerate the numerous defects imparted by doubled DNA content, and that these cells are therefore imparted with specific genetic dependencies that are not present in normal diploid cells (i.e. ploidy-specific lethality). These hypotheses will be tested in three specific aims. Aim 1: Use an innovative approach to rapidly quantitate the frequency and underlying cause of WGD in different tissues in vivo and determine if this frequency is affected by aging. Aim 2: Validate KIF18A, which encodes for a mitotic kinesin, as a ploidy-specific lethal gene in vivo, and use isogenic diploid/tetraploid cell models to perform an imaging- based phenotypic screen to identify small molecule inhibitors of KIF18A. Aim 3: Identify genetic aberrations (e.g. gene amplifications/deletions) that are significantly and specifically enriched in whole genome-doubled tumors, and mechanistically define how such alterations provide ploidy-specific growth advantages in vitro and in vivo. Successful completion of these aims will provide significant insight into the genesis, biology, and evolution of whole-genome doubled cells, as well as potentially reveal new and innovative therapeutic avenues to selectively kill whole-genome doubled cancer cells while sparing the normal healthy diploids from which they arose.
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