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Discovery of novel mechanisms of centrosome amplification and their therapeutic value in cancer
B.P. de Almeida1,2,, , G. Marteil3, M. Bettencourt-Dias3, N.L. Barbosa-Morais2
1 Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Faro, Portugal
2 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
3 Instituto Gulbenkian de Ciência, Oeiras, Portugal

Aim: To understand the mechanisms of centrosome amplification and their therapeutic value in cancer.

Introduction: Centrosomes are the major microtubule-organising centres of animal cells. Centrosome amplification (CA) – the presence of more than two centrosomes in a cell – is a common feature in cancer1 and was recently shown to be sufficient to drive tumourigenesis.2 Recent work from the Bettencourt-Dias Lab has identified a new recurrent feature of cancer cells: centriole over-elongation, which also promotes CA. However, origins of those abnormalities and their therapeutic value remain poorly understood.

Methods: We have screened the NCI-60 panel of human cancer cell lines3 for centriole number and individual length to test their frequency and interdependence. We have thereby also generated a metric capturing each abnormality level per cell line that we then correlated with the publicly available molecular (e.g. genomic, transcriptomic and proteomic) and drug-sensitivity quantitative profiles for that panel.

Results: Our single-centriole analyses showed that longer centrioles are more common in cells with CA and that cells do not control their overall centriolar mass when the centriole number increases. Moreover, cancer cell lines with longer centrioles proliferate slower due to an accumulation of cells in G1 phase, suggesting that centriole length defects could lead to a cell cycle delay in G1. In addition, our original genome-wide approach highlighted putative mechanisms associated with susceptibility to both abnormalities, such as the proteasome protecting cells from CA. Correlation with drug activity identified some compounds as potential therapeutic options to selectively target cells with higher incidence of centriole abnormalities.

Conclusion: This work provides the first single-centriole-level portrait of centriole abnormalities in cancer and contributes to the understanding of their molecular origins, namely by revealing novel molecular mechanisms in cell cycle biology. Given the cancer-specificity of these abnormalities, the identified compounds will inspire the development of drugs to selectively target cancer cells.

Acknowledgements: This work is supported by an EMBO Installation Grant to NLBM.

J.Y. Chan
A clinical overview of centrosome amplification in human cancers
Int J Biol Sci, 7 (2011), pp. 1122-1144
M.S. Levine
Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals
R.H. Shoemaker
The NCI60 human tumour cell line anticancer drug screen
Nat Rev Cancer, 6 (2006), pp. 813-823 http://dx.doi.org/10.1038/nrc1951

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