Identifying and harnessing mechanisms that are more strongly required for cancer cell division

Cancer is the leading cause of death in Canada, and remains difficult to treat since no two cancers are genetically the same. Cancer hallmarks describe the physiological changes that occur to give rise to metastatic cancer, and include uncontrolled cell proliferation and aneuploidy. Many of the current therapies target one or more of these hallmarks, but there is a need to expand the repertoire of available treatments. To do this, it is crucial to identify mechanisms controlling crucial physiological functions that are unique to cancer cells, which could be targeted to block their progression. In my thesis, I reveal that anillin, a cytokinesis protein, is more strongly required in cancer cells with hyperploidy compared to (near) diploid cells. Cytokinesis occurs at the end of mitosis to separate the daughter cells, due to the ingression of a contractile ring. Multiple pathways spatiotemporally control ring position to coordinate it with the segregating chromosomes. We previously discovered a chromatin-sensing pathway where Ran-GTP, which is enriched around chromatin, controls the levels of importins for the cortical recruitment of anillin to control ring position in HeLa cells. We hypothesized that this mechanism depends on ploidy, since HeLa cells are hypotriploid and we saw differences in anillin localization in cells with lower ploidy. In this thesis, I obtained evidence supporting this hypothesis by inducing an increase in ploidy in near diploid HCT116 cells where anillin is not strongly required, and revealing that this causes a change in anillin’s localization and its requirement for cytokinesis. I also show how importin-binding is involved for this requirement. These findings reveal that anillin and/or other chromatin sensing pathway components could make ideal targets for novel cancer therapies. In another project, we have been collaborating with Dr. Forgione’s lab (Chemistry and Biochemistry) to identify novel compounds with anti-cancer properties. His lab synthesized a family of thienoisoquinoline compounds, and we found several derivatives with high efficacy in cancer cells. We determined the mechanism of action of one of these derivatives, C75, in vitro and in cells. I found that C75 binds directly to tubulin and prevents microtubule polymerization in vitro. In cells, C75 disrupts the mitotic spindle, causing cells to arrest in mitosis. I also helped show that it can synergize with other microtubule-targeting drugs, including paclitaxel, which is currently being used to treat cancers. These findings reveal that thieonoisoquinoline compounds could be explored as a potential novel anti-cancer therapy.

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