The long-term goal of my research is to understand how centrosome amplification (CenAmp), the state of having more than two centrosomes in a cell, contributes to tumorigenesis. Centrosomes are microtubule- nucleating organelles that are important for forming the mitotic spindle and for proper chromosome segregation. Abnormalities in centrosome number are commonly observed in human cancer cells, where extra centrosomes lead to the chromosome segregation errors that are proposed to drive tumor formation. However, the tools to directly test whether extra centrosomes are sufficient to drive tumorigenesis had been lacking. To overcome this challenge, we created a novel mouse model in which the levels of Plk4, the master regulator of centrosome duplication, can be increased at will. I have shown that a modest increase in the levels of Plk4 promotes an irreversible increase in centrosome number in the mouse. Excitingly, preliminary data from our model demonstrate, for the first time, that CenAmp is sufficient to trigger spontaneous tumorigenesis. Despite being a common feature of cancers, in normal cells CenAmp causes a p53-dependent growth arrest. This arrest cannot be explained by any of the known p53 signaling pathways. Therefore, I propose that a centrosome surveillance pathway exists that protects against abnormal cell divisions by preventing the growth of cells with extra centrosomes. The goal of this application is to discover novel components of the centrosome surveillance pathway and determine how cancer cells bypass this pathway to form tumors in the presence of extra centrosomes.
In Aim 1, I will use a pooled, positive selection screen to uncover novel components of the centrosome surveillance pathway. We have already identified initial candidates in this pathway and we will define how these and other components act to inhibit the growth of cells with extra centrosomes.
In Aim 2, I will exploit bone marrow repopulation assays to test whether inactivation of the centrosome surveillance pathway co-operates with CenAmp to drive tumorigenesis in vivo. These studies will characterize a new tumor suppressor pathway, and thus contribute to the molecular understanding of oncogenesis.
Centrosomes are microtubule-organizing centers critical for faithful cell division. Abnormalities in centrosome number are commonly observed in human cancers, where they to contribute to cell division errors that are thought to drive malignant transformation. The work proposed here seeks to elucidate how cells respond to the presence of extra centrosomes and how this anomaly leads to the development of cancer.
| Levine, Michelle S; Holland, Andrew J (2018) The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev 32:620-638 |
| Levine, Michelle S; Bakker, Bjorn; Boeckx, Bram et al. (2017) Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals. Dev Cell 40:313-322.e5 |
| Levine, Michelle S; Holland, Andrew J (2014) Polo-like kinase 4 shapes up. Structure 22:1071-1073 |
