Centrosome amplification in cancer

The centrosome is the cell’s major microtubule-organizing center and plays an important role in mitosis, where it organizes the poles of the microtubule spindle apparatus that segregates the chromosomes. To maintain the fidelity of cell division, centrosome number must be strictly controlled. Cells begin the cycle with a single centrosome that duplicates only once to ensure cells have two copies of this organelle when they divide. This faithful control of centrosome number is deregulated in a wide array of tumor types, resulting in the acquisition of extra copies of centrosomes (referred to as centrosome amplification). Centrosome amplification causes mitotic errors in cultured cells that result in chromosome mis-segregation and chromosomal rearrangements. However, it remained untested whether supernumerary centrosomes actively drive tumorigenesis or whether they are simply a byproduct of cellular transformation. To address this important question in cancer biology, we created a mouse model in which centrosome amplification can be temporally induced at will. We showed that mice with extra centrosomes developed spontaneous tumors exhibiting widespread genomic instability, providing a causative link between centrosome amplification and tumorigenesis in mammals.

 

Selected papers

Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals.

Levine, M.S., Bakker, B., Boeckx, B., Moyett, J., Lu, J., Vitre, B., Spierings, D.C., Lansdorp, P.M., Cleveland, D.W., Lambrechts, D., Foijer, F. and Holland, A.J. Developmental Cell. 2017. 40(3): 313-22.

 

The impact of mitotic errors on cell proliferation and tumorigenesis.

Levine, M.S., and Holland, A.J. Genes and Development. 2018. 32(9-10): 620-38.

 

The emerging link between centrosome aberrations and metastasis.

LoMastro, G.M. and Holland, A.J. Developmental Cell. 2019. 49(3): 325-31.

 

ANKRD26 recruits PIDD1 to distal appendages to activate the PIDDosome following centrosome amplification. 

Evans, L.T., Anglen, T., Scott, P., Lukasik, K., Loncarek, J., Holland, A.J. In revision