Kræftens Bekæmpelse - KBVU - Undersøgelse af centrosomfejl i tetraploide celler som en cancer-initierende mekanisme

Aneuploidy and centrosome amplification are hallmarks of cancer. Cell division errors that lead to tetraploidization with centrosome amplifications are rare events. When they occur, the detrimental consequences of extra centrosomes associated with multipolar cell division, chromosome instability, or cell cycle arrest may critically reduce the viability of ‘founder cells’ and challenge the hypothesis of centrosome aberration as a cancer-initiating mechanism. Thiscalls for alternative hypotheses that explain how a sufficiently large subpopulation of ‘founder cells’ is able to survive at early phases of tumor development to stage a micro-evolutionary process that eventually develop a cancer phenotype with chromosome and centrosome aberrations. We hypothesize that an initiating mechanism of tumorigenesis involved incomplete centriole duplication coinciding with mitotic failure and tetraploidization or loss of extra centrosomes from tetraploid cells. We will take advantages of a recently developed selective PLK4 kinase inhibitor with the aim to study how PLK4 regulates centrosome biogenesis and how dysregulated centrosome biogenesis might contribute to cancer development. To this end, we plan to use quantitative phosphoproteomics to identify protein phosphorylation sites regulated during centrosome biogenesis. To test our hypothesis proposed above, we plan to establish tetraploid cells from primary cells with or without extra centrosomes. We will comparehow well they proliferate and how well they pass through mitosis using a combination of microscopy, phosphoproteomics, and protein proximity analyses. We will further test if protein imbalances in tetraploid cells without extra centrosomes eventually cause centrosome amplification associated with aneuploidy as a cancer initiating mechanism.