Patterns of selection against centrosome amplification in human cell lines

Abstract

The presence of extra centrioles, or centrosome amplification, is a hallmark of cancer cells. Centriole numbers in cancer cell populations appear to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is not known if the interaction between centriole overproduction and selection can quantitatively explain the intra-and inter-population heterogeneity in centriole numbers. Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles, in most cell lines. However, we do not detect significant differences in parameter estimates between different cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments. modelling | centrioles | cancer | evolutionary theory | inference Correspondence: mlouro@igc.gulbenkian.pt Dias Louro et al. | bioRχiv | January 24, 2020 | 1-19

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

“…Given the high-throughput data-driven approach deployed in this study, and the large amount of imaging data collected (>10,000 images across >300 FFPE tissues), we did not further inspect individual tissue regions for loss of centrosomes. However, consistent with the previous study 28 , we observed large variability in the spread of CA scores across all imaging fields within the same tissue, confirming that the CA phenotype displays marked inter-and intra-tissue heterogeneity in HGSOC tumours 24,28 . However, it is important to note that, although selected and imaged tissue samples were enriched for tumour regions, the presence of normal/stromal cells may influence the observed CA score and heterogeneity.…”

“…However, the vast majority of studies investigating mechanisms and consequences of CA have relied on experimentally induced or inhibited CA in cell lines and other model systems. Importantly, the high degree of variability in centrosome numbers observed across cancer cell populations suggests the existence of a CA "set point" or equilibrium 24 . This was first proposed following observations that cell lines recovered to their initial levels of CA after inhibition of centriole biogenesis 25 .…”

Biophysical and Quantitative Principles of Centrosome Biogenesis and Structure

“…SAS6 dynamically oligomerizes and dissociates until a complete ring is formed, establishing a single cartwheel hub. The first cartwheel elongates by depleting the SAS6 oligomer pool, which is likely to suppress the formation of any additional cartwheels(Dias Louro et al 2020). Figure adapted from images created with BioRender.…”

“…Takao et al 2019a). A recent study by DiasLouro et al (2020) proposed a different hypothesis for centriole number control in which elongation of the first assembled cartwheel depletes the pool of its building blocks, thus preventing extra cartwheels from forming (Figure…”