Finding the Achilles heel of cancer
Finding the Achilles heel of cancer
A research team led by Mónica Bettencourt Dias, from Instituto Gulbenkian de Ciência, discovered important features of cancer cells that may help clinicians fighting cancer. The researchers observed that the number and size of tiny structures that exist inside cells, called centrioles, are increased in the most aggressive sub-types of cancer. This study was published in Nature Communications*. Cancer is a very diverse disease with some tumours being more aggressive and more resistant to chemotherapy than others. Clinicians are eager to find novel diagnostic, prognostic and treatment tools that allow them to predict outcomes and treat patients in a more personalised way. The study now published may contribute to this process. About 100 times smaller than the cross section of a hair, centrioles have been called the cell´s "brain", as they play crucial roles in cell multiplication, movement and communication. Their number and size are highly controlled in normal cells. Since their discovery, more than one century ago, it has been proposed that an abnormal increase in the number of these structures may induce cancer. Bettencourt-Dias's team investigated the incidence of centriole abnormalities in human cancer cells. The researchers thoroughly analysed a panel of 60 human cancer lines originated from 9 distinct tissues. Their results reveal that cancer cells often have extra and longer centrioles, which are absent in normal cells. Importantly, the research team observed that supernumerary centrioles are more prevalent in aggressive breast - as the triple negative - and colon cancer. Also, the team discovered that longer centrioles are excessively active, which perturbs cell division and could favour cancer formation. "Our data confirm that deregulated number and size of centrioles inside cells is associated with malignant features. This finding may help establishing centriole properties as a way of classifying tumours in order to establish prognosis and predict treatment response", says Gaëlle Marteil, first author of this study and researcher at Bettencourt-Dias laboratory. What is the next step? "The cell lines that we analysed are already well characterized in terms of genetic changes and resistance to therapeutics. We are pursuing our studies in collaboration with Nuno Barbosa-Morais' team at Instituto de Medicina Molecular, in Lisbon, and Joana Paredes at I3S, in Porto, to explore new mechanisms and therapeutics that could target centrioles in cancer", adds Mónica Bettencourt-Dias. This study involved an international research team from Instituto Gulbenkian de Ciência, I3S- Instituto de Investigação e Inovação em Saúde (Portugal), IPATIMUP - Instituto de Patologia e Imunologia Molecular (Portugal), Instituto de Medicina Molecular (Portugal), Instituto Português de Oncologia (Portugal), and Dana-Faber Cancer Institute (USA). This work was funded by European Research Council (ERC), European Molecular Biology Organization (EMBO), Fundação para a Ciência e a Tecnologia(FCT, Portugal), and FCT- Harvard Medical School Program Portugal.
Authors and Affiliations:
Gaëlle Marteil; Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156, Oeiras, Portugal;
Adan Guerrero; Laboratorio Nacional de Microscopía Avanzada, Instituto de Biotecnología. Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, 62210, México
André F. Vieira; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Portugal. IPATIMUP - Instituto de Patologia e Imunologia Molecular, Universidade do Porto, 4200-135, Portugal;
Bernardo P. de Almeida; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, 1649-028, Portugal. Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Faro, 8005-139, Portugal;
Pedro Machado; European Molecular Biology Laboratory, Heidelberg, 69117, Germany;
Susana Mendonça; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Portugal. IPATIMUP - Instituto de Patologia e Imunologia Molecular, Universidade do Porto, 4200-135, Portugal;
Marta Mesquita; Instituto Português de Oncologia de Lisboa, Lisbon, 1099-023, Portugal.
Beth Villarreal; Novartis Institutes for BioMedical Research, Boston, MA 02139, USA.
Irina Fonseca; Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal.
Maria Eugenia Francia; Institut Pasteur de Montevideo, Montevideo, 11400, Uruguay;
Katharina Dores; Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal;
Nuno P. Martins; Advanced Imaging Facility, Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal;
Swadhin C. Jana; Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal;
Erin Tranfield; Electron Microscopy Facility, Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal.
Nuno L. Barbosa-Morais; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, 1649-028, Portugal;
Joana Paredes; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Portugal. IPATIMUP - Instituto de Patologia e Imunologia Molecular, Universidade do Porto, 4200-135, Portugal;
David Pellman; Dana-Faber Cancer Institute, Boston, MA 02215-5450, USA;
Susana A. Godinho; Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom;
Mónica Bettencourt-Dias; Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal;
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.
Journal: Nature Communications