MOLECULAR CIRCUITS CONTROLLING CENTRIOLE NUMBER IN SPACE AND TIME

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

Publication . Marteil, Gaelle; Guerrero, Adan; Vieira, Andre F.; de Almeida, Bernardo P.; Machado, Pedro; Mendonca, Susana; Mesquita, Marta; Villarreal, Beth; Fonseca, Irina; Francia, Maria E.; Dores, Katharina; Martins, Nuno P.; Jana, Swadhin C.; Tranfield, Erin M.; Barbosa-Morais, Nuno L.; Paredes, Joana; Pellman, David; Godinho, Susana A.; Bettencourt-Dias, Monica

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.

2018-03Journal article

Open Access