Over-elongation of centrioles in cancer promotes centriole amplification and chromosome missegregation

Abstract

Centrosomes are the major microtubule organising centres of animal cells. Deregulation in their number occurs in cancer and was shown to trigger tumorigenesis in mice. However, the incidence, consequence and origins of this abnormality are poorly understood. Here, we screened the NCI-60 panel of human cancer cell lines to systematically analyse centriole number and structure. Our screen shows that centriole amplification is widespread in cancer cell lines and highly prevalent in aggressive breast carcinomas. Moreover, we identify another recurrent feature of cancer cells: centriole size deregulation. Further experiments demonstrate that severe centriole over-elongation can promote amplification through both centriole fragmentation and ectopic procentriole formation. Furthermore, we show that overly long centrioles form over-active centrosomes that nucleate more microtubules, a known cause of invasiveness, and perturb chromosome segregation. Our screen establishes centriole amplification and size deregulation as recurrent features of cancer cells and identifies novel causes and consequences of those abnormalities.

Patterns of selection against centrosome amplification in human cell lines

“…Numeric aberrations of the centrosome and their putative link to cancer formation have long been described (3), although accurate quantifications of centriole numbers in tumor biopsies and cancer-derived cell lines have emerged only recently (9)(10)(11)(12) . To this day, the contribution of centrosomal anomalies to cancer development remain controversial, with some studies showing that higher numbers, via Plk4 overexpression, can initiate or aggravate tumorigenesis (28,29), and others showing that it is not sufficient and may even slow down progression (30,31).…”

“…In stark contrast with most proliferating cells, centriole numbers are often de-regulated during cancer development. In particular, cells with abnormally high numbers of centrioles are common in tumors and cancer-derived cell lines, and have been recently identified in pre-neoplastic tissues (8)(9)(10)(11)(12). Interestingly, within a single population of cancer cells, individual cells often carry different numbers of centrioles.…”

“…Interestingly, within a single population of cancer cells, individual cells often carry different numbers of centrioles. However, the number of centrioles per cell in the population seems to display a specific distribution depending on the cell type (9)(10)(11)(12). The source of this variability within and between cell populations is still poorly understood and calls for the development of quantitative approaches.…”

“…Here, we develop mathematical models of centriole overproduction and selection against centrosome amplification that are predicated on different assumptions on how supernumerary centrioles are produced and how selection operates. We use these models to analyze recently published data on representative cell lines of the progression from Barrett's esophagus to gastroesophageal adenocarcinoma (9) and the NCI-60 panel of cancer cell lines (10). These two data sets provide us with the opportunity to study how centriole number distributions vary along cancer progression, from pre-malignant to malignant stages, in the case of the Barrett's esophagus data set, and between different cancer types, in the NCI-60 data set.…”

Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

“…Cancer-derived cell lines have proven a useful resource to measure ongoing mechanisms driving chromosomal instability 7,9,12,30 . We assembled an array of eight HGSC lines, five previously identified as suitable models for HGSC (Cov318, Kuramochi, Ovkate, Ovsaho, Snu119) 27 and three obtained from recent confirmed HGSC patients (AOCS1 31 , G33 31 and G164) ( Table S1).…”