Cells sense mechanical factors in their environment to facilitate critical processes such as adhesion, differentiation, and migration. Accordingly, alteration of cellular forces is an emerging factor in diseases like atherosclerosis and cancer, which makes intuitive sense given that these diseases are often diagnosed by hardened arteries or detecting a lump that feels stiffer than the surrounding tissue. Indeed, an explosion of recent studies has revealed that increased resistance of the extracellular matrix (ECM) surrounding cells in breast cancer correlates with malignancy. Conversely, although tumors are stiffer, metastatic cells can be distinguished from non-invasive cancer cells by reduced cytoskeletal stiffness and increased deformability. Thus, altered mechanical forces in the microenvironment of cells, or its “mechano-some”, is a potentially targetable and quantifiable factor in disease, much like changes in the genome or proteome.
This lab is interested in the molecular mechanisms utilized by cell-surface receptors to sense and respond to force, which may lead to novel therapeutic avenues. One way they tackle the problem is to use structure/function studies to yield snapshots of mechanosensing domains of cell-surface receptors like Notch, polycystin-1, dystroglycan, and E-cadherin to understand how force might alter conformations of receptors to induce a response. To this end, the researchers express large amounts of putative mechanosensing domains for X-ray crystallography studies in E. coli, insect cells, and mammalian cells.