Current research - outline
In the lab, we are interested in the generation of biological form. Since the shape and internal organisation of each cell is determined by a combination of physics, biochemistry and information processing, we use a wide range of techniques to address the problem (including molecular biology, genetics, high-content RNA interference (RNAi) screening, live cell imaging, microfabrication, biophysical techniques and computational modeling). The wider aims of our research are to better understand the evolution of eukaryotic cell shape, to determine how cells regulate their form, and to determine how these processes contribute to normal tissue development and homeostasis and, when they go awry, to the evolution of metastatic cancer.
Cancer and the importance of mitotic cell rounding
Cancer is a disease in which individual clones of mutant cells expand without control even when spread far from their tissue of origin. This is made possible by mutations acquired by cancer cells during tumour evolution that break their normal dependency on the local cues which usually function to ensure that the behaviour of each cell is finely tuned to the requirements of its host tissue. As a result, while normal cells only divide to maintain tissue homeostasis, during tumour evolution cancer cells acquire a novel ability to divide under a range of conditions: in the face of compressive forces in a growing tumour and, to establish metastases, in new, poorly structured environments.
By studying mitotic rounding and cell division in different contexts, a major goal of our research is to understand the molecular and cellular mechanisms that make cancer cells both blind and resilient in the face of a changing environment. Mechanics plays a key role in this process, since the act of cell division is involves a series of dramatic actomyosin-dependent changes in cell shape and size. These begin at the very start of mitosis as cells stop moving, de-adhere from the substrate and round up to form rigid swollen spheres that provide a safe space in which to construct and orient their bipolar spindles. Then, once anaphase is triggered, cells elongate through polar relaxation as chromosomes move apart, before dividing into two as they exit mitosis. Ultimately, by characterising the genes and the biochemical, physical and geometrical constraints affecting mitotic progression in both normal and cancer cells, including cells isolated from patients, we hope to identify novel diagnostic and prognostic markers of cancer progression, and to identify strategies by which to selectively kill dividing metastatic cancer cells.
Tissue development and refinement
Genetically identical twins look remarkably similar. How the genome guides cell behavior during development to ensure this remains poorly understood. To get at this process we are trying to understand how actin-dependent changes in the shape of individual epithelial cells give rise to a well-ordered tissue during the completion of the development of the dorsal thorax of the fruit fly - a process we like to call tissue refinement. In recent work, using a combination of live cell imaging, genetics and computational modeling, we have used this approach to demonstrate a role for basal filopodia in tissue patterning and for cell delamination in the refinement of cell packing.
The evolution of the eukaryotic cell
Recently, we have begun applying the same approaches we have used to study cell shape in eukaryotes to archaea – using Sulfolobus as a model system. This new departure has been motivated: i) by our interest in the evolution of eukaryote cell organisation following publication of our new theoretical model on the origins of eukaryotic cell organistion, ii) by the recent discovery that the machinery determining eukaryote cell form has its origins in archaea, and iii) by the realisation that, despite the importance of archaea as one of the three domains of life, we know almost nothing about archaeal cell biology. Through this work we aim to improve our understanding of archael cell biology and of the origins and logic of eukaryotic cell architecture.