Date of Award
2024
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Cellular, Molecular and Biomedical Sciences
First Advisor
Jason K. Stumpff
Abstract
The vast majority of human cells are diploid and numerous controls exist to ensure this state is maintained through successive cell divisions. However, failure of these controls can result in chromosomal instability (CIN), a hallmark of human tumor cells. CIN cells must adapt to their abnormal aneuploid state, including higher dependency on kinesin motor protein, KIF18A. Although KIF18A is somewhat dispensable for accurate chromosome segregation in near-diploid cells, CIN cells are particularly sensitive to loss of KIF18A, inducing notable mitotic spindle defects and mitotic arrest. This mitotic arrest reduces CIN cell proliferation and is dependent on spindle assembly checkpoint (SAC) signaling. This suggests KIF18A could be a promising therapeutic target for CIN cells, however, a mechanistic explanation for why CIN cells depend on KIF18A remains poorly understood.This thesis focuses on addressing the molecular basis for KIF18A sensitivity in CIN cells using both candidate and screening approaches. Compared to chromosomally stable cells, CIN cells exhibit increased mitotic spindle microtubule plus-end assembly rates and KIF18A is a known regulator of microtubule dynamics. Thus, we first addressed that changes in microtubule dynamics may underlie CIN cell sensitivity to KIF18A inhibition. We found that reducing microtubule polymerization rates in CIN tumor cells via low-dose Taxol can partially rescue the mitotic defect phenotypes observed in CIN cells treated with KIF18A inhibitors. These results indicate that increased microtubule polymerization explains some, but not all, of the KIF18A sensitivity in CIN cells. To further address this question, we used RNAseq to investigate gene expression changes that could allow cells to bypass a dependence on KIF18A. We used these findings to generate new hypotheses relating to expression changes in genes associated with the SAC or that are affected by mutant p53 transcription. Collectively, this thesis contributes to uncovering the mechanisms behind CIN tumor cell sensitivity and resistance to KIF18A inhibition. This work not only adds to our understanding of KIF18A dependence in cancer but also may inform anti-cancer therapies and help pinpoint drug targets in the future.
Language
en
Number of Pages
53 p.
Recommended Citation
Belongia, Anna, "Investigating Sensitivity and Resistance of Tumor Cells to KIF18A Inhibition" (2024). Graduate College Dissertations and Theses. 1962.
https://scholarworks.uvm.edu/graddis/1962