The centrosome is the main microtubule-organising centre in animal cells; important to assemble a bipolar mitotic spindle ensuring proper chromosome segregation and genomic stability. Whereas correct centrosome number (1-2) is tightly maintained in normal cells, cancer cells usually have an increased number of centrosomes (>2), termed centrosome ampli cation. Centrosome ampli cation has been correlated with aneuploidy, increased tumour grade, chemoresistance and overall poor prognosis. Cancer cells primarily adapt to supernumerary centrosomes by clustering them into two poles resulting in a `normal' pseudo-bipolar mitosis. Undermining centrosome clustering is a potential target for cancer-speci c treatment. Indeed, depleting the kinesin HSET has already been shown to speci cally kill cancer cells by impairing the centrosome clustering mechanism. However, it is unclear whether this process requires adaptation or it is inherent to all cell types. Using a panel of non-transformed cell lines, we observed that cells expressing Ecadherin have ine cient clustering mechanisms compared to cell lines without E-cadherin. Loss of E-cadherin (siRNA/CRISPR) promotes centrosome clustering and survival of epithelial cells with multiple centrosomes. In addition, loss of DDR1, involved in regulating cortical contractility downstream of E-cadherin, increases centrosome clustering in epithelial cells. Using Atomic Force Microscopy we con rmed that indeed loss of E-cadherin leads to increased cortical contractility in mitotic cells. Inhibition of actomyosin contractility prevents e cient clustering in cells that do not express E-cadherin, further suggesting that it is important for this process. Loss of E-cadherin and DDR1 is strongly correlated with high levels of centrosome ampli cation in breast cancer cell lines suggesting that these changes are an important adaptation mechanism to centrosome amplification.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:766042 |
| Date | January 2017 |
| Creators | Rhys, Alexander Daniel |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://qmro.qmul.ac.uk/xmlui/handle/123456789/30943 |
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