Final Report Summary - CENTRIOLSTRUCTNUMBER (Control of Centriole Structure And Number) Centrioles are very small structures that exist within our cells and that make centrosomes, cilia and flagella. Centrosomes play a role in cell proliferation, cell polarity and signaling. Cilia and flagella are involved in cell signalling and movement. Centrosome, cilia and flagella defects are seen in many cancers and other conditions and diseases, such as infertility and polycystic kidney disease. The molecular mechanisms regulating centriole formation have only recently started to be unravelled, opening new ways to answer a wide range of questions that fascinate biologists for more than a century. In this grant we asked two fundamental questions that are central to human disease: how is centriole structure and number established and regulated in the eukaryotic cell? To address these questions we identified new molecular players and tested the role of these and known players in the context of specific mechanistic hypothesis, using in vitro and in vivo models. We uncovered several mechanisms that regulate centriole number and length, including positive and negative feedback loops in PLK4 regulation that control centriole number. PLK4 is a major trigger of centriole biogenesis and is highly deregulated in cancer, being now targeted in clinical trials in cancer. We identified that centrioles are very different in different tissues contributing to different functions. In particular, we found that differential regulation of core proteins, such as SAS6 and CEP290 contributes to the formation of different ciliary basis in different tissues, contributing to different ciliary functions. This may underlie why different mutations in the same gene may lead to different phenotypes in different patients. Finally, we uncovered that centrioles are not intrinsically stable, but their pericentriolar coating contributes to their stability and its removal causes their destabilization in certain tissues. This is particular important in the case of oocytes- if centrioles do not disappear the female is sterile. In order to understand how widespread centriole number and length deregulation are in cancer, we have screened the NCI-60 cell lines for centrosome abnormalities in a systematic manner. We found that centriole deregulation (number and size) is widespread in cancer and associated with poor prognosis. We are now collaborating with bioinformaticians to mine the data we obtained and to identify new causes of centriole amplification and forms of adaptation of cancer cells to centriole amplification. Since centriole amplification is only present in cancer cells, this provides a way of targeting specifically those cells.
