Our group uses a combination of biophysical and bioimaging techniques to study cell migration. Cell migration is a critical process in every living organism. For example, when wounds heal, skin cells migrate to close the wound. During cancer metastasis, cancer cells migrate and spread to a distant part of the body to initiate the formation of a new tumor. We develop novel assays to measure the biophysical properties of cell migration in three-dimensional microenvironments, and elucidate the signaling and gene regulatory networks that govern these properties, especially the role of the cytoskeleton. From these studies, we hope to identify novel therapeutic targets to perturb cell migration, which can eventually be translated into drugs to promote wound healing or stop cancer cell invasion.
Recently, we have looked at the migration of neutrophils. Neutrophils are white blood cells that play an important role in the host defence against pathogenic microbial agents. Under resting conditions, approximately 98% of the mature neutrophils in the body are stored within the bone marrow, with approximately 2% of the total mature neutrophils distributed in the blood stream and tissues. Upon exposure to inflammatory stimuli, neutrophils are rapidly mobilized from the bone marrow into the circulation, and are recruited to the site of inflammation where they carry out their functions and promote tissue remodelling. The distribution of neutrophils between bone marrow and blood compartment is mediated by egression and retention signals provided by chemokines CXCL2 and CXCL12, respectively. In bone marrow, CXCL12 constitutively expressed by stroma cells promotes neutrophil accumulation in the bone marrow through interaction with CXCR4. Moreover, the CXCR4-CXCL12 signalling axis also activates several signalling processes such as cell migration and proliferation.
Defects in neutrophil mobilization from the bone marrow into circulation leads to recurrent infections, as evinced by patients with the Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome. WHIM syndrome is an inherited primary immunodeficiency disease that subject the affected individual to recurrent bacterial infections due to low counts of most leukocytes, including neutrophils, circulating in the blood. WHIM patients expressing truncated CXCR4 display active receptor signalling that decays over a longer time as compared to WT leukocytes upon ligand stimulation. It has been shown that CXCL12-activated WHIM leukocytes show sustained activation of downstream signalling pathways such as pERK with greater signalling amplitude. Mutant leukocytes also exhibit higher sensitivity to CXCL12 as a larger percentage of cells migrated towards CXCL12 in transwell assays compared to WT cells.