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Uncovering previously unrecognized functions of mechanical force in extracellular matrix remodeling.

The stiff, the hard, and the brittle are harbingers of death. – Tao Te Ching trans. Stan Rosenthal

The benefits of flexibility, both literal and metaphorical, have been recognized for over 2,500 years. The material properties of our own bodies is governed largely by the extracellular matrix, a complex protein and carbohydrate network that gives shape to tissues and organs. Previously, the ECM was dismissed as passive glue that simply held cells together. We now know that failure to maintain the ECM leads not only to aching knees and wrinkles, but also to atherosclerosis, aneurism, and other cardiovascular diseases. Furthermore, the key step in cancer metastasis is the dissolution of the local ECM so that the cancer cells can escape to colonize the rest of the body.

We are using techniques ranging from single-molecule assays to live cell imaging to test the hypothesis that mechanical force is an unrecognized regulator of extracellular matrix (ECM) remodeling. We are particularly interested in the possibility that mechanical force may increase the susceptibility of ECM proteins to proteolysis by matrix metalloproteinases, enzymes that are the subject of intense medical interest due to their roles in cancer metastasis. This idea has been difficult to test due to the challenge of visualizing ECM structure and mechanical forces at the cellular length scale. Novel instruments and assays developed in our research group allow us to explore the interplay of force and ECM remodeling for the first time.

You can view our recent article about that here

Understanding how myosin uses chemical energy to generate force and motion


At right: A three bead optical tweezer setup to study the mechanism and function of motor proteins with nanometer spatial resolution and millisecond temporal resolution. The trace shows an example of an event (black) when the tweezer was oscillated (grey).

Design of new motor proteins



Role of intercellular forces in cell and developmental biology

The generation and detection of mechanical force is a central aspect of cell and developmental biology. Cells sense their physical surroundings by pulling on each other and the extracellular matrix (ECM). The resulting physical cues allow cells to communicate with each other, to coordinate complex collective movements, and to make critical decisions about cell growth and differentiation. Despite this central importance, the mechanisms by which cells exert and detect force remain poorly understood both in single cells and in whole organisms.

Our goal is to understand how cells generate, detect, and respond to tension at the molecular level. To do so, we are using new microscopy techniques that allow us to measure mechanical forces inside living cells, and even in whole organisms. The results from this project will be highly relevant to many aspects of human health, including heart disease, cancer metastasis, and the development of stem cell therapies, all of which are governed in part by the mechanical interactions of cells with their surroundings. (Above: An osmotic shock assay where a cell expands or contracts depending on the osmolarity of the solution it finds itself in. Cells use different mechanisms to protect themselves from situations of rapid increases or decreases in volume).

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