Patterns of selection against centrosome amplification in human cell lines

Abstract

The presence of extra centrioles, termed centrosome amplification, is a hallmark of cancer. The distribution of centriole numbers within a cancer cell population appears to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is unknown to date 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 human cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles in most 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.

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

“…However, 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. Neverthless, consistent with the previous study 26 , 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 22,26 . Both the high degree of CA heterogeneity and the confounding effect of stromal cells underscore the importance of acquiring multiple imaging fields per tumour sample and highlight a key strength of our imaging approach (see Supplementary Methods).…”

“…Most studies that have investigated mechanisms and consequences of CA have experimentally induced or inhibited CA in cell lines or other model systems predominantly in breast cancer models. However, the high degree of variability in centrosome numbers observed across cancer cell populations indicates the existence of a CA “set point” or equilibrium 22 and suggests that cell lines have different tolerance thresholds for CA and maintain centrosome numbers through an equilibrium of CA mechanisms and negative selection 23,24 . Consequently, the experimental induction or inhibition of CA may trigger a range of different cellular responses that would not otherwise be observed without these artificial perturbations.…”

Inhibiting centrosome clustering reduces cystogenesis and improves kidney function in autosomal dominant polycystic kidney disease

“…The balance of cells with CA in the population is maintained dynamically. A recent study by Dias Louro and colleagues ( 110 ) employed a model selection approach to infer patterns of CA and selection in a diverse panel of human cancer cell lines. Their results indicate that the fraction of cells with CA in these populations is at equilibrium, and maintained by a balance of centrosome overproduction and negative selection (apoptosis) of cells with CA, reminiscent of mutation-selection balance.…”

High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders

“…Conceivably, centrosome amplification can promote tumorigenesis in mouse models [ 58 ], but evidence for the lack of such an effect also exists [ 59 ]. This apparent controversy likely results at least in part from strong selection against extra centrioles in proliferating cells [ 60 ].…”