Our lab studies fundamental aspects of cellular mechanobiology, i.e., how cells sense the mechanical features of the extracellular matrix, and how these features affect cellular behavior under normal and disease conditions. We are particularly interested in the underlying biophysical aspects of cancer.
Our aim is to identify new avenues to attack cancer, with the premise that the mechanobiological cellular pathways (the adhesion and cytoskeletal systems) are vulnerable to treatment since they have much less redundancy compared to biochemical pathways.
We use specialized substrates with micro-fabricated pillar arrays to track the forces that the cells apply at their edges to test matrix rigidity. In this way we are able to show that forces are produced by micron-scale contractile units that pinch the matrix. Numerous components are involved in formation of these contractile units, including adhesion, cytoskeletal, and signaling proteins.
Loss of tropomyosin leads to the formation of much smaller integrin adhesions (demonstrated here by fluorescence imaging of GFP-paxillin – one of the most common adhesion proteins). This result is somewhat counter-intuitive because the prevalent model is that larger adhesions promote growth. The solution could come from studies of the kinetics of force production and adhesion formation. Potentially, it is not the adhesion sizes per se that are important, but rather the number of mechanosensors in the adhesions and the amount of force that they experience.
Left: Tropomyosin2.1, an important regulator of cellular forces, localizes to the edges of non-malignant breast epithelial cells (MCF-10A), but is absent from breast cancer cells (MDA-MB-231). Right: the absence of tropomyosin leads to an almost complete loss of contractile units, and to the production of higher forces than normal (green vectors show contractile units, i.e., two pillars moving towards each other; red vectors show non-contractile unit forces).
Cells sense the mechanical features of the extracellular matrix by applying forces to it through integrin adhesions. This process (termed ‘mechanosensing’) occurs on short time- and length-scales, but it affects global cellular functions that occur on timescales of hours-to-days. In the lab, we are studying how the mechanical signals are transmitted to affect cellular decisions under normal conditions, and how this process is altered in cancer cells which effectively ignore the mechanical properties of the matrix. Read more…