The dynamic shape of an animal cell is determined by the interplay of intra- and extracellular forces. In the lab we explore the molecular, cellular and physical processes involved using interdisciplinary approaches including molecular biology, genetics, high-content RNA interference (RNAi)
screening, live cell imaging, automated image analysis, microfabrication,
biophysical techniques and computational modeling. The aim of our research is to better
understand 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 characterizing the genes and the biochemical, physical and geometrical constraints affecting mitotic progression in both normal and cancer cells, including CTCs 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
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
epithelial cell delamination in the refinement of cell packing.
We are currently recruiting a post-doc to study the mechanics of cell division. If you are interested, please contact us.