CHIAM Keng Hwee
Senior Principal Investigator
Senior Post Doc Research Fellow
YIP Ai Kia
Post Doc Research Fellow
FARM Hui Jia
JUN Myeongjun, NASSAR Lamees
The group uses a combination of biophysical and bioinformatics tools to study cell migration. Cell migration is a critical process in every living organism, central to, for example, the morphogenesis of embryos, formation of tissues and organs, wound repair, as well as in less welcoming scenarios such as cancer metastasis. Currently, the group focuses on:
- Development of quantitative assays to measure the biophysical properties of cell migration,
- Quantitative experiments and modelling of amoeboid migration and chemotaxis,
- Quantitative modelling of collective cell migration,
- Quantitative experiments and modelling of bacteria swimming and chemotaxis.
Development of Quantitive Assays to measure the Biophysical Properties of Cell Migration
Most cell migration studies have been carried out on two-dimensional substrates and are therefore not physiological, even though a lot has been known from such studies about the formation of integrin-mediated cell-matrix adhesion and flat two-dimensional protrusions such as filopodia and lamellipodia. On the other hand, not much is known about how cells migrate in three-dimensional environments. This is particularly important for some tumor cells, which has been known to form bleb-like protrusions and change their shapes in a manner similar to amoebae; the shape changes then allow the tumor cells to squeeze through the pores in the extracellular matrix and invade.
We have been collaborating with wet labs in various A*STAR research institutes to develop a three-dimensional assay that mimics in vivo conditions. We will use this assay to screen for inhibitors of in vivo cell migration. Their effects on cell migration can then be assessed. We will automatically track the cell movement and measure cell speed, directional persistence, as well as traction force magnitudes that the cell exerts on the substrate. These measurements serve as quantitative indicators of the cell’s migratory potential.
Quantitative Experiments and Modelling of Amoeboid Migration and Chemotaxis
Tumor cells have been observed to migrate using the so-called amoeboid mode, characterized by its independence from integrin-mediated adhesion to the substrate. This is different from the more commonly studied mode of mesenchymal migration, characterized by actin polymerization and focal adhesion assembly. We are studying amoeboid migration and chemotaxis, both experimentally and computationally. For example, we have shown that amoeboid cells can migrate via a “chimneying” mechanism by generating anchoring stresses normal to the substrate and shearing stresses at protrusions that shift the cell body forward resulting in cell movement. In Figure 1, we show examples of the traction stress distribution that amoeboid cells exert on their substrates. Such quantitative calculations allow us to identify new modes of migration.
We will also use inhibitor libraries to screen for and uncover the signaling networks that regulate the amoeboid mode of migration and chemotaxis. Knowledge of such signaling networks will eventually allow us to uncover novel gene functions implicated in migration and chemotaxis as well as identify targets to inhibit tumor invasion during cancer metastasis.
Quantitative Modelling of Collective Cell Migration
In multicellular organisms, certain cells such as epithelial cells migrate collectively as a group instead of individually. The skin, for example, is comprised of striated layers of epithelial cells. We are interested in developing quantitative models of how an epithelial cell sheet can maintain its integrity while at the same time accommodating for individual cell movement and rearrangement, cell division, and cell death. Such models require one to understand the molecular mechanisms of cytoskeletal rearrangement and cell-cell adhesion, and how these molecular processes influence the mechanical properties of the cells. Conversely, it is also important to account for the effects of mechanics on cell signaling and hence cytoskeletal rearrangement and regulation of cell-cell adhesion. For example, in Figure 2, we show the results from a simulation of how cells in a piece of tissue can sort themselves in response to an external morphogen while still maintaining tissue integrity.
One specific problem that such a quantitative model can be applied to is to study how an epithelial layer can function as a barrier. This is a problem that is motivated by the consumer care industry. For example, we are interested in using our quantitative models to compute the permeation into the skin of a particular compound such as those found in a cream or lotion that is being applied topically onto the skin. Our quantitative models will allow us to study the effects of perturbing specific signaling pathways so as to modify the ability of a particular chemical to permeate into the skin epithelial layer. We expect such computations to be useful to the consumer care industry where there is a general trend to move away from animal testing to in silico product testing.
Quantitative Experiments and Modelling of Bacteria Swimmind abd Chemotaxis
Turning now from eukaryotic cells to bacterial cells, we are also using similar biophysical modelling tools to study bacteria cell motility and how individual bacteria swarm to form a biofilm. In particular, we focus on Pseudomonas aeruginosa, whose motility has not been well understood. P. aeruginosa is a species of clinical relevance because it is an opportunistic pathogen that colonizes medical equipment such as catheters as well as the pulmonary and urinary tracts resulting in infection. We are developing biophysical methods to quantitatively characterize the mechanism for P. aeruginosa motility, swarming, and finally the switch from the planktonic to the biofilm phenotype. For example, we have carefully imaged and analyzed the rotational properties of the single bacterial flagellum, and have discovered a novel mode of swimming that is unique to this species. In Figure 3, we show an example of this analysis. We can next study mutant strains to understand the genetics governing the motility phenotypes observed.
Biophysical Modeling Members
Dr. CHIAM Keng Hwee
|Dr. CHIAM Keng Hwee||Principal Investigator|
|Dr. ZENG Yukai||Postdoctoral Fellow|
|Dr. YIP Ai Kia||Postdoctoral Fellow|
|Ms. FARM Hui Jia||Research Officer|
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