Adaptation of human cell populations to different levels of centriole amplification involves a two-step response

Centrioles are the main components of cilia and centrosomes, which play a central role in cell proliferation and signalling. Their number is 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 affect centriole number dynamics is poorly described.

PLK4, a key regulator of centriole biogenesis, is often overexpressed in cancer and is associated with worse prognosis in breast cancer. Here we show that centriole amplification cannot be sustained in cultured MCF10A breast cells exposed to low and high levels of chronic PLK4 overexpression. We observed a short-term response in which negative selection and reduction in PLK4 mRNA limit centriole amplification. This was followed by long-term adaptation in which a rise in PLK4 mRNA levels was decoupled from accumulation of the protein at the centrosome. Furthermore, adaptation was dose-dependent. Populations evolved in low-overexpression conditions retained the ability to generate extra centrioles when PLK4 was further overexpressed, whereas centriole overproduction was irreversibly inhibited in populations evolved under high PLK4 overexpression. Taken together, our data reveal a two step mode of centriole number regulation and suggest that differences in the level of PLK4 overexpression may condition cancer evolution.