Adaptation of human cell populations to different levels of centriole amplification

Abstract

Centrioles are the main components of cilia and centrosomes, which play a central role in cell division and signalling. Their numbers are strictly regulated. Centriole amplification, or the presence of extra centrioles, often occurs in tumours and leads to aneuploidy and altered signalling and has been associated with cancer development and malignancy. Negative selection of cells with extra centrioles prevents numerical errors from expanding in the population, resulting in an overproduction-selection balance. However, how chronic perturbation of key centriolar regulators affects centriole number dynamics is poorly described. PLK4, a key regulator of centriole biogenesis, is often overexpressed in cancer. Here, we studied the long-term dynamics of cell populations exposed to different levels of PLK4 overexpression. We measured absolute and relative fitness in the evolving populations, quantified centriole numbers over time, as well as various aspects of the immediate response to centriole amplification. Our experiments indicated negative selection against cells with extra centrioles and outcompetition of PLK4-overexpressing cells by a cell line carrying a truncated form of PLK4, that does not amplify centrioles. In populations where cells carrying the truncated form of PLK4 were absent, cells overexpressing full-length PLK4 maintained the capacity to amplify centrioles over the course of experimental evolution and, strikingly, converge to the same degree of centriole amplification regardless of the level of PLK4 overexpression. Our results support a population-level response to centrosome amplification to control centriole amplification levels. Future work is necessary to further characterise this response and the mechanisms that allow cell populations to maintain centriole amplification.