1. How centrosomes and cilia are built and maintained

We investigate the regulation of centriole biogenesis and stability across cell types and organisms. Our lab identified PLK4 as the master trigger of centriole formation (Bettencourt-Dias et al., 2004; 2005) and showed that centrioles can also form de novo (Rodrigues-Martins et al., 2007; Lopes et al., 2015; Nabais et al., 2021). We uncovered mechanisms controlling centriole number via feedback loops, protein degradation, and CDK1 regulation of PLK4 (Cunha-Ferreira et al., 2009, 2013; Zitouni et al., 2016; Gouveia et al., 2018). We are now investigating how centriole de novo biogenesis is further regulated.

Our work further revealed that centriole maintenance is an active process, requiring Polo kinase/PLK1 and pericentriolar material (Pimenta-Marques et al., 2016; Pimenta-Marques & Perestrelo et al., 2024). Using Drosophila sensory neurons, human non-transformed cells, and cancer models, we showed that centrioles adapt structurally to function (Chen et al., 2015; Jana et al., 2018) and that ciliary homeostasis and function depends on regulators such as IFT88 (Werner & Ramos et al., 2024). We are now further investigating the role of proteostasis in centriole and cilia maintenance.

2. How centrioles and cilia have evolved

Combining comparative genomics and cell biology, we identified the ancestral centriole in the Last Eukaryotic Common Ancestor (LECA) and traced its stepwise evolution (Carvalho-Santos et al., 2010; 2011; Ito et al., 2019). In collaboration with P. Keeling (UBC, Canada), H. Goodson (UND, USA), and J. Wideman (UA, USA), we are supported by the Moore Foundation to study the evolutionary transitions of basal bodies and microtubule-organizing centers (MTOCs). This collaborative effort uses spatial proteomics and evolutionary cell biology to uncover how basal bodies diversified from flagellar organizers to central players in mitosis and meiosis.

3. How centrosomes and cilia are deregulated in disease

Centrosome and cilia abnormalities are frequent in cancer and ciliopathies. We demonstrated that centriole amplification and size deregulation are early cancer features linked to poor prognosis (Lopes et al., 2018; Marteil et al., 2018; Moreno et al. bioRxiv 2023). We identified a pan-cancer centrosome amplification signature associated with genomic instability and patient outcome (Almeida et al., 2019), and proposed mechanisms that allow tumor cells to tolerate centrosome amplification (Louro et al., 2021; bioRxiv 2023). In collaboration with M. João Amorim (UCP, PT), we are also investigating how viral infections perturb centriole and cilia homeostasis and how this feeds back into disease progression.