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Investigating the link between centrosomes, stem cells and cancer

Final Report Summary - CENTROSTEMCANCER (Investigating the link between centrosomes, stem cells and cancer)

The centrosome is the major microtubule organising center of animal cells. It consists of a pair of centrioles surrounded by a mesh of more than one hundred proteins, the pericentriolar material, which is the site of MT nucleation. Centrosomes function as organising centers during mitosis or polarity establishment and as basal bodies for cilia assembly. The Basto lab is interested in characterising key molecular players in centrosome and cilia biogenesis and to understand how mutations in centrosome or cilia components impact on development and lead to the establishment of disease.
Our group has been interested in understanding the consequences of centrosome amplification, which is defined by the presence of more then two centrosomes in a cell. Centrosome amplification is a hallmark of human tumours, but whether it is a cause or a consequence it remained to be determined. Using Drosophila melanogaster as a model organism combined with genetic and biochemistry approaches and with state-of the-art microscopy, we have found that centrosome amplification is a tumour initiating event. Further we have unravelled the presence of tissue specific responses to centrosome amplification. In self-renewing stem cells, centrosome amplification causes mis-positioned of the mitotic spindle, which leads to errors in cell fate specification. Consequently, this leads to the expansion of the stem cell pool at the expense of differentiating cells. On the other hand, centrosome amplification in epithelial tissues does not result in spindle positioning defects but rather in the generation of multipolar mitotic spindles and abnormal karyotypes that can lead to transformation. We have also identified the underlying mechanisms that sustain these differential responses.
Our work has significantly contributed to understand how centrosome dysfunction impact on the microtubule cytoskeleton leading to loss of cell fitness and transformation.