Biology subjects

Bettencourt Dias, M.

Publications and source records attributed to Bettencourt Dias, M..

4 recordsLinked to original sources

bioRxiv2024

Adaptation of human cell populations to different levels of centriole amplification involves a two-step response

Centrioles are the main components of cilia and centrosomes, which play a central role in cell division and signalling. Their numbers are strictly regulated. Centriole amplification, or the presence of extra centrioles, often occurs in tumours and leads to aneuploidy and altered signalling and has been associated with cancer development and malignancy. Negative selection of cells with extra centrioles prevents numerical errors from expanding in the population, resulting in an overproduction-selection balance. However, how chronic perturbation of key centriolar regulators affects centriole number dynamics is poorly described. PLK4, a key regulator of centriole biogenesis, is often overexpressed in cancer. Here, we studied the long-term dynamics of cell populations exposed to different levels of PLK4 overexpression. We measured absolute and relative fitness in the evolving populations, quantified centriole numbers over time, as well as various aspects of the immediate response to centriole amplification. Our experiments indicated negative selection against cells with extra centrioles and outcompetition of PLK4-overexpressing cells by a cell line carrying a truncated form of PLK4, that does not amplify centrioles. In populations where cells carrying the truncated form of PLK4 were absent, cells overexpressing full-length PLK4 maintained the capacity to amplify centrioles over the course of experimental evolution and, strikingly, converge to the same degree of centriole amplification regardless of the level of PLK4 overexpression. Our results support a population-level response to centrosome amplification to control centriole amplification levels. Future work is necessary to further characterise this response and the mechanisms that allow cell populations to maintain centriole amplification.

cell biology↗

bioRxiv2022

Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype

Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of non-tumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4s role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-induced anoikis resistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also induces anoikis resistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion. Our work shows, for the first time, that high expression levels of Plk4 induce anoikis resistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.

cancer biology↗

bioRxiv2021

Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1

The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral-facial-digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits, and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein cep164. Myosin VI depletion in non-tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be causally linked to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies.

cell biology↗

bioRxiv2020

Plk4 triggers autonomous de novo centriole biogenesis and maturation

Centrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally and numerically regulated by the cell cycle and the presence of mature centrioles. However, in certain cell-types, centrioles assemble de novo, yet by poorly understood mechanisms. Here, we established a controlled system to investigate de novo centriole biogenesis, using Drosophila melanogaster egg explants overexpressing Polo-like kinase 4 (Plk4), a trigger for centriole biogenesis. We show that at high Plk4 concentration, centrioles form de novo, mature and duplicate, independently of cell cycle progression and of the presence of other centrioles. Plk4 concentration determines the kinetics of centriole assembly. Moreover, our results suggest Plk4 operates in a switch-like manner to control the onset of de novo centriole formation, and that distinct biochemical kinetics regulate de novo and canonical biogenesis. Finally, we investigated which other factors modulate de novo centriole assembly and reveal that proteins of the pericentriolar matrix (PCM) promote biogenesis, likely by locally concentrating critical components.

cell biology↗