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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. Cancer cells are characterised by abnormalities in the number of centrosomes and this phenotype is linked with tumorigenesis. Here the authors report centriole length deregulation in a subset of cancer cell lines and suggest a link with subsequent alterations in centriole numbers and chromosomal instability.

Cancer kills one in five people each year in western societies, therefore clinicians are eager to find novel diagnostic, prognostic and therapeutic tools to predict outcomes and treat patients. More than a century ago, Theodor Boveri suggested that numerical abnormalities in the centrosome, the major Microtubule Organizing Centre (MTOC) in animal cells, cause abnormal cell division and tumour formation. Extra centrosomes promote aberrant cell divisions, which can induce the formation of more than two non-viable daughter cells. However cancer cells often divide successfully and survive by clustering (i.e. gathering) their supernumerary centrosomes. Our previous work has indeed shown that centrosome defects are widespread in the NCI-60 panel of cancer cell lines and that centrosome clustering is the main but not the sole coping mechanism with centrosome amplification. With this thesis, I wanted to investigate a) how widespread clustering is in the NCI-60 panel, b) what alternative coping mechanisms exist and how widespread they are, and c) how cells divide in presence of alternative mechanisms. To answer these questions, we screened the centrosome clustering ability of 27 cancer cell lines using immunofluorescence images of mitotic cells displaying centrosome amplification. This work showed that centrosome clustering is widespread in cancer and highlighted the presence of alternative mechanisms, i.e. centrosome extrusion and inactivation, for the first time in cancer. Furthermore, I observed that most of the cell lines divide in a bipolar fashion by combining the different coping mechanisms. Further studies are now required to highlight the cellular and molecular machineries regulating the alternative mechanisms as they represent exploitable Achilles’ heels of cancer cells for the development of innovative drugs to selectively kill cancer.

The presence of supernumerary centrosomes is a hallmark of cancer and is frequently observed in aggressive tumors. Cancer cells with centrosome amplification achieve pseudo-bipolar spindles through specific coping mechanisms in order to survive. However, their distribution and prevalence in cancer remain largely unknown. Here, using the NCI60 panel of cancer cell lines, we show that the presence of coping strategies correlates with centrosome amplification, with the clustering of extra-centrosomes within the two spindle poles being the most widespread mechanism. Moreover, we report an association between centrosome clustering ability and the epithelial-to-mesenchymal transition (EMT) and observe that the induction of mesenchymal characteristics in breast cancer cells with centrosome amplification promotes clustering. Furthermore, we unveil hematological malignancies, which lack epithelial characteristics, as the most proficient in centrosome clustering. Finally, we show that acute lymphoblastic leukemia is particularly sensitive to targeting clustering through inhibition of the spindle assembly checkpoint. Our study reveals how centrosome clustering and EMT collaborate to promote carcinogenesis, suggesting new possibilities to treat tumors with low epithelial characteristics, in particular leukemias.Competing Interest StatementThe authors have declared no competing interest.